Triazolopyridines and triazolopyrazines as lsd1 inhibitors

ABSTRACT

The present invention is directed to [1,2,4]triazolo[4,3-a]pyridine and [1,2,4]triazolo[4,3-a]pyrazine derivatives which are LSD1 inhibitors useful in the treatment of diseases such as cancer.

FIELD OF THE INVENTION

The present invention is directed to [1,2,4]triazolo[4,3-a]pyridine and[1,2,4]triazolo[4,3-a]pyrazine derivatives which are LSD1 inhibitorsuseful in the treatment of diseases such as cancer.

BACKGROUND OF THE INVENTION

Epigenetic modifications can impact genetic variation but, whendysregulated, can also contribute to the development of various diseases(Portela, A. and M. Esteller, Epigenetic modifications andhuman disease.Nat Biotechnol, 2010. 28(10): p. 1057-68; Lund, A. H. and M. vanLohuizen, Epigenetics and cancer. Genes Dev, 2004. 18(19): p. 2315-35).Recently, in depth cancer genomics studies have discovered manyepigenetic regulatory genes are often mutated or their own expression isabnormal in a variety of cancers (Dawson, M. A. and T. Kouzarides,Cancer epigenetics: from mechanism to therapy. Cell, 2012. 150(1): p.12-27; Waldmann, T. and R. Schneider, Targeting histonemodifications—epigenetics in cancer. Curr Opin Cell Biol, 2013. 25(2):p. 184-9; Shen, H. and P. W. Laird, Interplay between the cancer genomeand epigenome. Cell, 2013. 153(1): p. 38-55). This implies epigeneticregulators function as cancer drivers or are permissive fortumorigenesis or disease progression. Therefore, deregulated epigeneticregulators are attractive therapeutic targets.

One particular enzyme which is associated with human diseases is lysinespecific demethylase-1 (LSD1), the first discovered histone demethylase(Shi, Y., et al., Histone demethylation mediated by the nuclear amineoxidase homolog LSD1. Cell, 2004. 119(7): p. 941-53). It consists ofthree major domains: the N-terminal SWIRM which functions in nucleosometargeting, the tower domain which is involved in protein-proteininteraction, such as transcriptional co-repressor, co-repressor ofRE1-silencing transcription factor (CoREST), and lastly the C terminalcatalytic domain whose sequence and structure share homology with theflavin adenine dinucleotide (FAD)-dependent monoamine oxidases (i.e.,MAO-A and MAO-B) (Forneris, F., et al., Structural basis of LSD1-CoRESTselectivity in histone H3 recognition. J Biol Chem, 2007. 282(28): p.20070-4; Anand, R. and R. Marmorstein, Structure and mechanism oflysine-specific demethylase enzymes. J Biol Chem, 2007. 282(49): p.35425-9; Stavropoulos, P., G. Blobel, and A. Hoelz, Crystal structureand mechanism of human lysine-specific demethylase-1. Nat Struct MolBiol, 2006. 13(7): p. 626-32; Chen, Y., et al., Crystal structure ofhuman histone lysine-specific demethylase 1 (LSD1). Proc Natl Acad SciUSA, 2006. 103(38): p. 13956-61). LSD1 also shares a fair degree ofhomology with another lysine specific demethylase (LSD2) (Karytinos, A.,et al., A novel mammalian flavin-dependent histone demethylase. J BiolChem, 2009. 284(26): p. 17775-82). Although the biochemical mechanism ofaction is conserved in two isoforms, the substrate specificities arethought to be distinct with relatively small overlap. The enzymaticreactions of LSD1 and LSD2 are dependent on the redox process of FAD andthe requirement of a protonated nitrogen in the methylated lysine isthought to limit the activity of LSD1/2 to mono- and di-methylatedlysines at the position of 4 or 9 of histone 3 (H3K4 or H3K9). Thesemechanisms make LSD1/2 distinct from other histone demethylase families(i.e. Jumonji domain containing family) that can demethylate mono-, di-,and tri-methylated lysines through alpha-ketoglutarate dependentreactions (Kooistra, S. M. and K. Helin, Molecular mechanisms andpotential functions of histone demethylases. Nat Rev Mol Cell Biol,2012. 13(5): p. 297-311; Mosammaparast, N. and Y. Shi, Reversal ofhistone methylation: biochemical and molecular mechanisms of histonedemethylases. Annu Rev Biochem, 2010. 79: p. 155-79).

Methylated histone marks on H3K4 and H3K9 are generally coupled withtranscriptional activation and repression, respectively. As part ofcorepressor complexes (e.g., CoREST), LSD1 has been reported todemethylate H3K4 and repress transcription, whereas LSD1, in nuclearhormone receptor complex (e.g., androgen receptor), may demethylate H3K9to activate gene expression (Metzger, E., et al., LSD1 demethylatesrepressive histone marks to promote androgen-receptor-dependenttranscription. Nature, 2005. 437(7057): p. 436-9; Kahl, P., et al.,Androgen receptor coactivators lysine-specific histone demethylase 1 andfour and a half LIM domain protein 2 predict risk of prostate cancerrecurrence. Cancer Res, 2006. 66(23): p. 11341-7). This suggests thesubstrate specificity of LSD1 can be determined by associated factors,thereby regulating alternative gene expressions in a context dependentmanner. In addition to histone proteins, LSD1 may demethylatenon-histone proteins. These include p53 (Huang, J., et al., p53 isregulated by the lysine demethylase LSD1. Nature, 2007. 449(7158): p.105-8), E2F (Kontaki, H. and I. Talianidis, Lysine methylation regulatesE2F1-induced cell death. Mol Cell, 2010. 39(1): p. 152-60), STAT3 (Yang,J., et al., Reversible methylation of promoter-bound STAT3 byhistone-modifying enzymes. Proc Natl Acad Sci USA, 2010. 107(50): p.21499-504), Tat (Sakane, N., et al., Activation of HIV transcription bythe viral Tat protein requires a demethylation step mediated bylysine-specific demethylase 1 (LSD1/KDM1). PLoS Pathog, 2011. 7(8): p.e1002184), and myosin phosphatase target subunit 1 (MYPT1) (Cho, H. S.,et al., Demethylation of RB regulator MYPT1 by histone demethylase LSD1promotes cell cycle progression in cancer cells. Cancer Res, 2011.71(3): p. 655-60). The lists of non-histone substrates are growing withtechnical advances in functional proteomics studies. These suggestadditional oncogenic roles of LSD1 beyond regulating chromatinremodeling. LSD1 also associates with other epigenetic regulators, suchas DNA methyltransferase 1 (DNMT1) (Wang, J., et al., The lysinedemethylase LSD1 (KDM1) is required for maintenance of global DNAmethylation. Nat Genet, 2009. 41(1): p. 125-9) and histone deacetylases(HDACs) complexes (Hakimi, M. A., et al., A core-BRAF35 complexcontaining histone deacetylase mediates repression of neuronal-specificgenes. Proc Natl Acad Sci USA, 2002. 99(11): p. 7420-5; Lee, M. G., etal., Functional interplay between histone demethylase and deacetylaseenzymes. Mol Cell Biol, 2006. 26(17): p. 6395-402; You, A., et al.,CoREST is an integral component of the CoREST-human histone deacetylasecomplex. Proc Natl Acad Sci USA, 2001. 98(4): p. 1454-8). Theseassociations augment the activities of DNMT or HDACs. LSD1 inhibitorsmay therefore potentiate the effects of HDAC or DNMT inhibitors. Indeed,preclinical studies have shown such potential already (Singh, M. M., etal., Inhibition of LSD1 sensitizes glioblastoma cells to histonedeacetylase inhibitors. Neuro Oncol, 2011. 13(8): p. 894-903; Han, H.,et al., Synergistic re-activation of epigenetically silenced genes bycombinatorial inhibition of DNMTs and LSD1 in cancer cells. PLoS One,2013. 8(9): p. e75136).

LSD1 has been reported to contribute to a variety of biologicalprocesses, including cell proliferation, epithelial-mesenchymaltransition (EMT), and stem cell biology (both embryonic stem cells andcancer stem cells) or self-renewal and cellular transformation ofsomatic cells (Chen, Y., et al., Lysine-specific histone demethylase 1(LSD1): A potential molecular target for tumor therapy. Crit RevEukaryot Gene Expr, 2012. 22(1): p. 53-9; Sun, G., et al., Histonedemethylase LSD1 regulates neural stem cell proliferation. Mol CellBiol, 2010. 30(8): p. 1997-2005; Adamo, A., M. J. Barrero, and J. C.Izpisua Belmonte, LSD1 and pluripotency: a new player in the network.Cell Cycle, 2011. 10(19): p. 3215-6; Adamo, A., et al., LSD1 regulatesthe balance between self-renewal and differentiation in human embryonicstem cells. Nat Cell Biol, 2011. 13(6): p. 652-9). In particular, cancerstem cells or cancer initiating cells have some pluripotent stem cellproperties that contribute to the heterogeneity of cancer cells. Thisfeature may render cancer cells more resistant to conventionaltherapies, such as chemotherapy or radiotherapy, and then developrecurrence after treatment (Clevers, H., The cancer stem cell: premises,promises and challenges. Nat Med, 2011. 17(3): p. 313-9; Beck, B. and C.Blanpain, Unravelling cancer stem cell potential. Nat Rev Cancer, 2013.13(10): p. 727-38). LSD1 was reported to maintain an undifferentiatedtumor initiating or cancer stem cell phenotype in a spectrum of cancers(Zhang, X., et al., Pluripotent Stem Cell Protein Sox2 ConfersSensitivity to LSD1 Inhibition in Cancer Cells. Cell Rep, 2013. 5(2): p.445-57; Wang, J., et al., Novel histone demethylase LSD1 inhibitorsselectively target cancer cells with pluripotent stem cell properties.Cancer Res, 2011. 71(23): p. 7238-49). Acute myeloid leukemias (AMLs)are an example of neoplastic cells that retain some of their lessdifferentiated stem cell like phenotype or leukemia stem cell (LSC)potential. Analysis of AML cells including gene expression arrays andchromatin immunoprecipitation with next generation sequencing (ChIP-Seq)revealed that LSD1 may regulate a subset of genes involved in multipleoncogenic programs to maintain LSC (Harris, W. J., et al., The histonedemethylase KDM1A sustains the oncogenic potential of MLL-AF9 leukemiastem cells. Cancer Cell, 2012. 21(4): p. 473-87; Schenk, T., et al.,Inhibition of the LSD1 (KDM1A) demethylase reactivates theall-trans-retinoic acid differentiation pathway in acute myeloidleukemia. Nat Med, 2012. 18(4): p. 605-11). These findings suggestpotential therapeutic benefit of LSD1 inhibitors targeting cancershaving stem cell properties, such as AMLs.

Overexpression of LSD1 is frequently observed in many types of cancers,including bladder cancer, NSCLC, breast carcinomas, ovary cancer,glioma, colorectal cancer, sarcoma including chondrosarcoma, Ewing'ssarcoma, osteosarcoma, and rhabdomyosarcoma, neuroblastoma, prostatecancer, esophageal squamous cell carcinoma, and papillary thyroidcarcinoma. Notably, studies found over-expression of LSD1 wassignificantly associated with clinically aggressive cancers, forexample, recurrent prostate cancer, NSCLC, glioma, breast, colon cancer,ovary cancer, esophageal squamous cell carcinoma, and neuroblastoma. Inthese studies, either knockdown of LSD1 expression or treatment withsmall molecular inhibitors of LSD1 resulted in decreased cancer cellproliferation and/or induction of apoptosis. See, e.g., Hayami, S., etal., Overexpression of LSD1 contributes to human carcinogenesis throughchromatin regulation in various cancers. Int J Cancer, 2011. 128(3): p.574-86; Lv, T., et al., Over-expression of LSD1 promotes proliferation,migration and invasion in non-small cell lung cancer. PLoS One, 2012.7(4): p. e35065; Serce, N., et al., Elevated expression of LSD1(Lysine-specific demethylase 1) during tumour progression frompre-invasive to invasive ductal carcinoma of the breast. BMC ClinPathol, 2012. 12: p. 13; Lim, S., et al., Lysine-specific demethylase 1(LSD1) is highly expressed in ER-negative breast cancers and a biomarkerpredicting aggressive biology. Carcinogenesis, 2010. 31(3): p. 512-20;Konovalov, S. and I. Garcia-Bassets, Analysis of the levels oflysine-specific demethylase 1 (LSD1) mRNA in human ovarian tumors andthe effects of chemical LSD1 inhibitors in ovarian cancer cell lines. JOvarian Res, 2013. 6(1): p. 75; Sareddy, G. R., et al., KDM1 is a noveltherapeutic target for the treatment of gliomas. Oncotarget, 2013. 4(1):p. 18-28; Ding, J., et al., LSD1-mediated epigenetic modificationcontributes to proliferation and metastasis of colon cancer. Br JCancer, 2013. 109(4): p. 994-1003; Bennani-Baiti, I. M., et al.,Lysine-specific demethylase 1 (LSD1/KDM1A/AOF2/BHC110) is expressed andis an epigenetic drug target in chondrosarcoma, Ewing's sarcoma,osteosarcoma, and rhabdomyosarcoma. Hum Pathol, 2012. 43(8): p. 1300-7;Schulte, J. H., et al., Lysine-specific demethylase 1 is stronglyexpressed in poorly differentiated neuroblastoma: implications fortherapy. Cancer Res, 2009. 69(5): p. 2065-71; Crea, F., et al., Theemerging role of histone lysine demethylases in prostate cancer. MolCancer, 2012. 11: p. 52; Suikki, H. E., et al., Genetic alterations andchanges in expression of histone demethylases in prostate cancer.Prostate, 2010. 70(8): p. 889-98; Yu, Y., et al., High expression oflysine-specific demethylase 1 correlates with poor prognosis of patientswith esophageal squamous cell carcinoma. Biochem Biophys Res Commun,2013. 437(2): p. 192-8; Kong, L., et al., Immunohistochemical expressionof RBP2 and LSD1 in papillary thyroid carcinoma. Rom J Morphol Embryol,2013. 54(3): p. 499-503.

Recently, the induction of CD86 expression by inhibiting LSD1 activitywas reported (Lynch, J. T., et al., CD86 expression as a surrogatecellular biomarker for pharmacological inhibition of the histonedemethylase lysine-specific demethylase 1. Anal Biochem, 2013. 442(1):p. 104-6). CD86 expression is a marker of maturation of dendritic cells(DCs) which are involved in antitumor immune response. Notably, CD86functions as a co-stimulatory factor to activate T cell proliferation(Greaves, P. and J. G. Gribben, The role of B7 family molecules inhematologic malignancy. Blood, 2013. 121(5): p. 734-44; Chen, L. and D.B. Flies, Molecular mechanisms of T cell co-stimulation andco-inhibition. Nat Rev Immunol, 2013. 13(4): p. 227-42).

In addition to playing a role in cancer, LSD1 activity has also beenassociated with viral pathogenesis. Particularly, LSD1 activity appearsto be linked with viral replications and expressions of viral genes. Forexample, LSD1 functions as a co-activator to induce gene expression fromthe viral immediate early genes of various type of herpes virusincluding herpes simplex virus (HSV), varicella zoster virus (VZV), andβ-herpesvirus human cytomegalovirus (Liang, Y., et al., Targeting theJMJD2 histone demethylases to epigenetically control herpesvirusinfection and reactivation from latency. Sci Transl Med, 2013. 5(167):p. 167ra5; Liang, Y., et al., Inhibition of the histone demethylase LSD1blocks alpha-herpesvirus lytic replication and reactivation fromlatency. Nat Med, 2009. 15(11): p. 1312-7). In this setting, a LSD1inhibitor showed antiviral activity by blocking viral replication andaltering virus associated gene expression.

Recent studies have also shown that the inhibition of LSD1 by eithergenetic depletion or pharmacological intervention increased fetal globingene expression in erythroid cells (Shi, L., et al., Lysine-specificdemethylase 1 is a therapeutic target for fetal hemoglobin induction.Nat Med, 2013. 19(3): p. 291-4; Xu, J., et al., Corepressor-dependentsilencing of fetal hemoglobin expression by BCL11A. Proc Natl Acad SciUSA, 2013. 110(16): p. 6518-23). Inducing fetal globin gene would bepotentially therapeutically beneficial for the disease ofβ-globinopathies, including β-thalassemia and sickle cell disease wherethe production of normal β-globin, a component of adult hemoglobin, isimpaired (Sankaran, V. G. and S. H. Orkin, The switch from fetal toadult hemoglobin. Cold Spring Harb Perspect Med, 2013. 3(1): p. a011643;Bauer, D. E., S. C. Kamran, and S. H. Orkin, Reawakening fetalhemoglobin: prospects for new therapies for the beta-globin disorders.Blood, 2012. 120(15): p. 2945-53). Moreover, LSD1 inhibition maypotentiate other clinically used therapies, such as hydroxyurea orazacitidine. These agents may act, at least in part, by increasingγ-globin gene expression through different mechanisms.

In summary, LSD1 contributes to tumor development by altering epigeneticmarks on histones and non-histone proteins. Accumulating data havevalidated that either genetic depletion or pharmacological interventionof LSD1 normalizes altered gene expressions, thereby inducingdifferentiation programs into mature cell types, decreasing cellproliferation, and promoting apoptosis in cancer cells. Therefore, LSD1inhibitors alone or in combination with established therapeutic drugswould be effective to treat the diseases associated with LSD1 activity.

SUMMARY OF THE INVENTION

The present invention is directed to, inter alia, a compound of FormulaI:

or a pharmaceutically acceptable salt thereof, wherein constituentvariables are defined herein.

The present invention is further directed to a pharmaceuticalcomposition comprising a compound of Formula I and at least onepharmaceutically acceptable carrier.

The present invention is further directed to a method of inhibiting LSD1comprising contacting the LSD1 with a compound of Formula I.

The present invention is further directed to a method of treating anLSD1-mediated disease in a patient comprising administering to thepatient a therapeutically effective amount of a compound of Formula I.

DETAILED DESCRIPTION

The present invention provides, inter alia, LSD1-inhibiting compoundssuch as a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

X is N or CR^(X);

Y is (a) C═O and Z is NR^(Z) or (b) Y is CR³ and Z is N;

wherein the bond between Y and Z represented by

is a single bond in the case of (a) and a double bond in the case of(b);

Ring A is C₆₋₁₀ aryl or 5-10 membered heteroaryl comprising carbon and1, 2, 3, or 4 heteroatoms selected from N, O, and S, wherein said C₆₋₁₀aryl and 5-10 membered heteroaryl are each optionally substituted by 1,2, 3, or 4 substituents independently selected from R^(A);

Ring B is C₆₋₁₀ aryl; 5-10 membered heteroaryl comprising carbon and 1,2, 3 or 4 heteroatoms selected from N, O, and S; C₃₋₁₀ cycloalkyl; or4-10 membered heterocycloalkyl comprising carbon and 1, 2, 3 or 4heteroatoms selected from N, O, and S; wherein said C₆₋₁₀ aryl, 5-10membered heteroaryl, C₃₋₁₀ cycloalkyl, and 4-10 memberedheterocycloalkyl are each optionally substituted by 1, 2, 3, or 4substituents independently selected from R^(B);

R¹ is halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, Cy¹,CN, OR^(a1), SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1),OC(O)R^(b1), OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1), C(═NR^(e1))R^(b1),C(═NR^(e1))NR^(c1)R^(d1), NR^(c1)C(═NR^(e1))NR^(c1)R^(d1),NR^(c1)S(O)R^(b1), NR^(c1)S(O)₂R^(b1), NR^(c1)S(O)₂NR^(c1)R^(d1),S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1), or S(O)₂NR^(c1)R^(d1),wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are eachoptionally substituted with 1, 2, or 3 substituents independentlyselected from Cy¹, halo, CN, OR^(a1), SR^(a1), C(O)R^(b1),C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1), OC(O)NR^(c1)R^(d1),NR^(c1)R^(d1), NR^(c1)C(o)R^(b1), NR^(c1)C(O)OR^(a1),NR^(c1)C(O)NR^(c1)R^(d1), C(═NR^(e1))R^(b1), C(═NR^(e1))NR^(c1)R^(d1),NR^(c1)C(═NR^(e1))NR^(c1)R^(d1), NR^(c1)S(O)R^(b1), NR^(c1)S(O)₂R^(b1),NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1),and S(O)₂NR^(c1)R^(d1);

R³ is H, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,Cy², CN, OR^(a2), SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2),NR^(c2)R^(d2), NR^(c2)C(O)R^(b2), NR^(c2)C(O)OR^(a2),NR^(c2)C(O)NR^(c2)R^(d2), C(═NR^(e2))R^(b2), C(═NR^(e2))NR^(c2)R^(d2),NR^(c2)C(═NR^(e2))NR^(c2)R^(d2) NR^(c2)S(O)R^(b2), NR^(c2)S(O)₂R^(b2),NR^(c2)S(O)₂NR^(c2)R^(d2), S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2),or S(O)₂NR^(c2)R^(d2), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl are each optionally substituted with 1, 2, or 3 substituentsindependently selected from Cy², halo, CN, OR^(a2), SR^(a2), C(O)R^(b2),C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2), OC(O)NR^(c2)R^(d2),NR^(c2)R^(d2), NR^(c2)C(O)R^(b2), NR^(c2)C(O)OR^(a2),NR^(c2)C(O)NR^(c2)R^(d2), C(═NR^(e2))R^(b2), C(═NR^(e2))NR^(c2)R^(d2),NR^(c2)C(═NR^(e2))NR^(c2)R^(d2), NR^(c2)S(O)R^(b2), NR^(c2)S(O)₂R^(b2),NR^(c2)S(O)₂NR^(c2)R^(d2), S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2),and S(O)₂NR^(c2)R^(d2);

each R^(A) is independently selected from halo, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, CN, NO₂, OR^(a4), SR^(a4),C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4),OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),NR^(c4)C(O)OR^(a4), NR^(c4)C(O)NR^(c4)R^(d4), C(═NR^(e4))R^(b4),C(═NR^(e4))NR^(c4)R^(d4), NR^(c4)C(═NR^(e4))NR^(c4)R^(d4),NR^(c4)S(O)R^(b4), NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4),S(O)R^(b4), S(O)NR^(c4)R^(d4), S(O)₂R^(b4), and S(O)₂NR^(c4)R^(d4),wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are eachoptionally substituted by 1, 2, or 3, substituents independentlyselected from halo, C₁₋₆ haloalkyl, CN, NO₂, OR^(a4), SR^(a4),C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4),OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),NR^(c4)C(O)OR^(a4), NR^(c4)C(O)NR^(c4)R^(d4), C(═NR^(e4))R^(b4),C(═NR^(e4))NR^(c4)R^(d4), NR^(c4)C(═NR^(e4))NR^(c4)R^(d4)NR^(c4)S(O)R^(b4), NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4),S(O)R^(b4), S(O)NR^(c4)R^(d4), S(O)₂R^(b4), and S(O)₂NR^(c4)R^(d4);

each R^(B) is independently selected from Cy³, halo, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, CN, NO₂, OR^(a5), SR^(a5),C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5),OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5), NR^(c5)C(O)R^(b5),NR^(c5)C(O)OR^(a5), NR^(c5)C(O)NR^(c5)R^(d5), C(═NR^(e5))R^(b5),C(═NR^(e5))NR^(c5)R^(d5), NR^(c5)C(═NR^(e5))NR^(c5)R^(d5),NR^(c5)S(O)R^(b5), NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5),S(O)R^(b5), S(O)NR^(c5)R^(d5), S(O)₂R^(b5), and S(O)₂NR^(c5)R^(d5),wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are eachoptionally substituted by 1, 2, or 3 substituents independently selectedfrom Cy³, halo, C₁₋₆ haloalkyl, CN, NO₂, OR^(a5), SR^(a5), C(O)R^(b5),C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5), OC(O)NR^(c5)R^(d5),NR^(c5)R^(d5), NR^(c5)C(O)R^(b5), NR^(c5)C(O)OR^(a5),NR^(c5)C(O)NR^(c5)R^(d5), C(═NR^(e5))R^(b5), C(═NR^(e5))NR^(c5)R^(d5),NR^(c5)C(═NR^(e5))NR^(c5)R^(d5), NR^(c5)S(O)R^(b5), NR^(c5)S(O)₂R^(b5),NR^(c5)S(O)₂NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5), S(O)₂R^(b5),and S(O)₂NR^(c5)R^(d5);

R^(X) is H, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, CN, OR^(a8), SR^(a8), C(O)R^(b8), C(O)NR^(c8)R^(d8),C(O)OR^(a8), OC(O)R^(b8), OC(O)NR^(c8)R^(d8), NR^(c8)R^(d8),NR^(c8)C(O)R^(b8), NR^(c8)C(O)OR^(a8), NR^(c8)C(O)NR^(c8)R^(d8),C(═NR^(e8))R^(b8), C(═NR^(e8))NR^(c8)R^(d8),NR^(c8)C(═NR^(e8))NR^(c8)R^(d8), NR^(c8)S(O)R^(b8), NR^(c8)S(O)₂R^(b8),NR^(c8)S(O)₂NR^(c8)R^(d8), S(O)R^(b8), S(O)NR^(c8)R^(d8), S(O)₂R^(b8),or S(O)₂NR^(c8)R^(d8);

R^(Z) is H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, orCy⁴, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are eachoptionally substituted with 1, 2, 3, 4, or 5 substituents independentlyselected from Cy⁴, halo, CN, OR^(a3), SR^(a3), C(O)R^(b3),C(O)NR^(c3)R^(d3), C(O)OR^(a3), OC(O)R^(b3), OC(O)NR^(c3)R^(d3),NR^(c3)R^(d3), NR^(c3)C(O)R^(b3), NR^(c3)C(O)OR^(a3),NR^(c3)C(O)NR^(c3)R^(d3), C(═NR^(e3))R^(b3), C(═NR^(e3))NR^(c3)R^(d3),NR^(c3)C(═NR^(e3))NR^(c3)R^(d3), NR^(c3)S(O)R^(b3), NR^(c3)S(O)₂R^(b3),NR^(c3) S(O)₂NR^(c3)R^(d3), S(O)R^(b3), S(O)NR^(c3)R^(d3), S(O)₂R^(b3),and S(O)₂NR^(c3)R^(d3);

each Cy¹, Cy², Cy³, Cy⁴, and Cy⁵ is independently selected from C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, and 4-10 memberedheterocycloalkyl, each of which is optionally substituted with 1, 2, 3,or 4 substituents independently selected from R^(Cy);

each R^(Cy) is selected from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄cyanoalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₄ alkyl-,C₃₋₇ cycloalkyl-C₁₋₄ alkyl-, (5-6 membered heteroaryl)-C₁₋₄ alkyl-, (4-7membered heterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a6), SR^(a6),C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6), OC(O)R^(b6),OC(O)NR^(c6)R^(d6), C(═NR^(e6))NR^(c6)R^(d6),NR^(c6)C(═NR^(e6))NR^(c6)R^(d6), NR^(c6)R^(d6), NR^(c6)C(O)R^(b6),NR^(c6)C(O)OR^(a6), NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)S(O)R^(b6),NR^(c6)S(O)₂R^(b6), NR^(c6)S(O)₂NR^(c6)R^(d6), S(O)R^(b6),S(O)NR^(c6)R^(d6), S(O)₂R^(b6), and S(O)₂NR^(c6)R^(d6), wherein saidC₁₋₄ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₄ alkyl-,C₃₋₇ cycloalkyl-C₁₋₄ alkyl-, (5-6 membered heteroaryl)-C₁₋₄ alkyl-, and(4-7 membered heterocycloalkyl)-C₁₋₄ alkyl- are each optionallysubstituted by 1, 2, or 3 substituents independently selected from C₁₋₄alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, halo, CN, NO₂, OR^(a6), SR^(a6),C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6), OC(O)R^(b6),OC(O)NR^(c6)R^(d6), C(═NR^(e6))NR^(c6)R^(d6),NR^(c6)C(═NR^(e6))NR^(c6)R^(d6), NR^(c6)R^(d6), NR^(c6)C(O)R^(b6),NR^(c6)C(O)OR^(a6), NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)S(O)R^(b6),NR^(c6)S(O)₂R^(b6), NR^(c6)S(O)₂NR^(c6)R^(d6), S(O)R^(b6),S(O)NR^(c6)R^(d6), S(O)₂R^(b6), and S(O)₂NR^(c6)R^(d6);

each R^(a1) is independently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, and Cy⁵, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl are each optionally substituted with 1, 2, or 3 substituentsindependently selected from Cy⁵, halo, CN, OR^(a7), SR^(a7), C(O)R^(b7),C(O)NR^(c7)R^(d7), C(O)OR^(a7), OC(O)R^(b7), OC(O)NR^(c7)R^(d7),NR^(c7)R^(d7), NR^(c7)C(O)R^(b7), NR^(c7)C(O)OR^(a7),NR^(c7)C(O)NR^(c7)R^(d7), C(═NR^(e7))R^(b7), C(═NR^(e7))NR^(c7)R^(d7),NR^(c7)C(═NR^(e7))NR^(c7)R^(d7), NR^(c7)S(O)R^(b7), NR^(c7)S(O)₂R^(b7),NR⁷S(O)₂NR^(c7)R^(d7), S(O)R^(b7), S(O)NR^(c7)R^(d7), S(O)₂R^(b7), andS(O)₂NR^(c7)R^(d7);

each R^(b1), R^(c1), and R^(d1) is independently selected from H, C₁₋₆alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄alkyl-, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- are each optionally substituted with 1, 2,3, 4, or 5 substituents independently selected from C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄ cyanoalkyl, halo, CN, OR^(a8), SR^(a8), C(O)R^(b8),C(O)NR^(c8)R^(d8), C(O)OR^(a8), OC(O)R^(b8), OC(O)NR^(c8)R^(d8),NR^(c8)R^(d8), NR^(c8)C(O)R^(b8), NR^(c8)C(O)NR^(c8)R^(d8),NR^(c8)C(O)OR^(a8), C(═NR^(e8))NR^(c8)R^(d8),NR^(c8)C(═NR^(e8))NR^(c8)R^(d8), S(O)R^(b8), S(O)NR^(c8)R^(d8),S(O)₂R^(b8), NR^(c8)S(O)₂R^(b8), NR^(c8)S(O)₂NR^(c8)R^(d8), andS(O)₂NR^(c8)R^(d8);

or any R^(c1) and R^(d1) together with the N atom to which they areattached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, or 3 substituents independentlyselected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₁₋₆ haloalkyl,halo, CN, OR^(a8), SR^(a8), C(O)R^(b8), C(O)NR^(c8)R^(d8), C(O)OR^(a8),OC(O)R^(b8), OC(O)NR^(c8)R^(d8), NR^(c8)R^(d8), NR^(c8)C(O)R^(b8),NR^(c8)C(O)NR^(c8)R^(d8), NR^(c8)C(O)OR^(a8), C(═NR^(e8))NR^(c8)R^(d8),NR^(c8)C(═NR^(e8))NR^(c8)R^(d8), S(O)R^(b8), S(O)NR^(c8)R^(d8),S(O)₂R^(b8), NR^(c8)S(O)₂R^(b8), NR^(c8)S(O)₂NR^(c8)R^(d8), andS(O)₂NR^(c8)R^(d8), wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-6 membered heteroaryl areeach optionally substituted by 1, 2, or 3 substituents independentlyselected from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, CN,OR^(a8), SR^(a8), C(O)R^(b8), C(O)NR^(c8)R^(d8), C(O)OR^(a8),OC(O)R^(b8), OC(O)NR^(c8)R^(d8), NR^(c8)R^(d8), NR^(c8)C(O)R^(b8),NR^(c8)C(O)NR^(c8)R^(d8), NR^(c8)C(O)OR^(a8), C(═NR^(e8))NR^(c8)R^(d8),NR^(c8)C(═NR^(e8))NR^(c8)R^(d8), S(O)R^(b8), S(O)NR^(c8)R^(d8),S(O)₂R^(b8), NR^(c8)S(O)₂R^(b8), NR^(c8)S(O)₂NR^(c8)R^(d8), andS(O)₂NR^(c8)R^(d8);

each R^(a2), R^(b2), R^(c2), and R^(d2) is independently selected fromH, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are each optionallysubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, halo, CN, OR^(a8),SR^(a8), C(O)R^(b8), C(O)NR^(c8)R^(d8), C(O)OR^(a8), OC(O)R^(b8),OC(O)NR^(c8)R^(d8), NR^(c8)R^(d8), NR^(c8)C(O)R^(b8),NR^(c8)C(O)NR^(c8)R^(d8), NR^(c8)C(O)OR^(a8), C(═NR^(e8))NR^(c8)R^(d8),NR^(c8)C(═NR^(e8))NR^(c8)R^(d8), S(O)R^(b8), S(O)NR^(c8)R^(d8),S(O)₂R^(b8), NR^(c8)S(O)₂R^(b8), NR^(c8)S(O)₂NR^(c8)R^(d8), andS(O)₂NR^(c8)R^(d8);

or any R^(c2) and R^(d2) together with the N atom to which they areattached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, or 3 substituents independentlyselected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₁₋₆ haloalkyl,halo, CN, OR^(a8), SR^(a8), C(O)R^(b8), C(O)NR^(c8)R^(d8), C(O)OR^(a8),OC(O)R^(b8), OC(O)NR^(c8)R^(d8), NR^(c8)R^(d8), NR^(c8)C(O)R^(b8),NR^(c8)C(O)NR^(c8)R^(d8), NR^(c8)C(O)OR^(a8), C(═NR^(e8))NR^(c8)R^(d8),NR^(c8)C(═NR^(e8))NR^(c8)R^(d8), S(O)R^(b8), S(O)NR^(c8)R^(d8),S(O)₂R^(b8), NR^(c8)S(O)₂R^(b8), NR^(c8)S(O)₂NR^(c8)R^(d8), andS(O)₂NR^(c8)R^(d8), wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-6 membered heteroaryl areeach optionally substituted by 1, 2, or 3 substituents independentlyselected from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, CN,OR^(a8), SR^(a8), C(O)R^(b8), C(O)NR^(c8)R^(d8), C(O)OR^(a8),OC(O)R^(b8), OC(O)NR^(c8)R^(d8), NR^(c8)R^(d8), NR^(c8)C(O)R^(b8),NR^(c8)C(O)NR^(c8)R^(d8), NR^(c8)C(O)OR^(a8), C(═NR^(e8))NR^(c8)R^(d8),NR^(c8)C(═NR^(e8))NR^(c8)R^(d8), S(O)R^(b8), S(O)NR^(c8)R^(d8),S(O)₂R^(b8), NR^(c8)S(O)₂R^(b8), NR^(c8)S(O)₂NR^(c8)R^(d8), andS(O)₂NR^(c8)R^(d8);

each R^(a3), R^(b3), R^(c3), and R^(d3), is independently selected fromH, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are each optionallysubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, halo, CN, OR^(a8),SR^(a8), C(O)R^(b8), C(O)NR^(c8)R^(d8), C(O)OR^(a8), OC(O)R^(b8),OC(O)NR^(c8)R^(d8), NR^(c8)R^(d8), NR^(c8)C(O)R^(b8),NR^(c8)C(O)NR^(c8)R^(d8), NR^(c8)C(O)OR^(a8), C(═NR^(e8))NR^(c8)R^(d8),NR^(c8)C(═NR^(e8))NR^(c8)R^(d8), S(O)R^(b8), S(O)NR^(c8)R^(d8),S(O)₂R^(b8), NR^(c8)S(O)₂R^(b8), NR^(c8)S(O)₂NR^(c8)R^(d8), andS(O)₂NR^(c8)R^(d8);

or any R^(c3) and R^(d3), together with the N atom to which they areattached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, or 3 substituents independentlyselected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo, CN, OR^(a8), SR^(a8),C(O)R^(b8), C(O)NR^(c8)R^(d8), C(O)OR^(a8), OC(O)R^(b8),OC(O)NR^(c8)R^(d8), NR^(c8)R^(d8), NR^(c8)C(O)R^(b8),NR^(c8)C(O)NR^(c8)R^(d8), NR^(c8)C(O)OR^(a8), C(═NR^(e8))NR^(c8)R^(d8),NR^(c8)C(═NR^(e8))NR^(c8)R^(d8), S(O)R^(b8), S(O)NR^(c8)R^(d8),S(O)₂R^(b8), NR^(c8)S(O)₂R^(b8), NR^(c8)S(O)₂NR^(c8)R^(d8), andS(O)₂NR^(c8)R^(d8);

each R^(a4), R^(b4), R^(c4), and R^(d4) is independently selected fromH, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl, whereinsaid C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are each optionallysubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄ cyanoalkyl, halo, CN, OR^(a8),SR^(a8), C(O)R^(b8), C(O)NR^(c8)R^(d8), C(O)OR^(a8), OC(O)R^(b8),OC(O)NR^(c8)R^(d8), NR^(c8)R^(d8), NR^(c8)C(O)R^(b8),NR^(c8)C(O)NR^(c8)R^(d8), NR^(c8)C(O)OR^(a8), C(═NR^(e8))NR^(c8)R^(d8),NR^(c8)C(═NR^(e8))NR^(c8)R^(d8), S(O)R^(b8), S(O)NR^(c8)R^(d8),S(O)₂R^(b8), NR^(c8)S(O)₂R^(b8), NR^(c8)S(O)₂NR^(c8)R^(d8), andS(O)₂NR^(c8)R^(d8);

or any R^(c4) and R^(d4) together with the N atom to which they areattached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, or 3 substituents independentlyselected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo, CN, OR^(a8), SR^(a8),C(O)R^(b8), C(O)NR^(c8)R^(d8), C(O)OR^(a8), OC(O)R^(b8),OC(O)NR^(c8)R^(d8), NR^(c8)R^(d8), NR^(c8)C(O)R^(b8),NR^(c8)C(O)NR^(c8)R^(d8), NR^(c8)C(O)OR^(a8), C(═NR^(e8))NR^(c8)R^(d8),NR^(c8)C(═NR^(e8))NR^(c8)R^(d8), S(O)R^(b8), S(O)NR^(c8)R^(d8),S(O)₂R^(b8), NR^(c8)S(O)₂R^(b8), NR^(c8)S(O)₂NR^(c8)R^(d8), andS(O)₂NR^(c8)R^(d8);

each R^(a5), R^(b5), R^(c5), and R^(d5) is independently selected fromH, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are each optionallysubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, halo, CN, OR^(a8),SR^(a8), C(O)R^(b8), C(O)NR^(c8)R^(d8), C(O)OR^(a8), OC(O)R^(b8),OC(O)NR^(c8)R^(d8), NR^(c8)R^(d8), NR^(c8)C(O)R^(b8),NR^(c8)C(O)NR^(c8)R^(d8), NR^(c8)C(O)OR^(a8), C(═NR^(e8))NR^(c8)R^(d8),NR^(c8)C(═NR^(e8))N^(c8)R^(d8), S(O)R^(b8), S(O)NR^(c8)R^(d8),S(O)₂R^(b8), NR^(c8)S(O)₂R^(b8), NR^(c8)S(O)₂NR^(c8)R^(d8), andS(O)₂NR^(c8)R^(d8);

or any R^(c5) and R^(d5) together with the N atom to which they areattached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, or 3 substituents independentlyselected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₁₋₆ haloalkyl,halo, CN, OR^(a8), SR^(a8), C(O)R^(b8), C(O)NR^(c8)R^(d8), C(O)OR^(a8),OC(O)R^(b8), OC(O)NR^(c8)R^(d8), NR^(c8)R^(d8), NR^(c8)C(O)R^(b8),NR^(c8)C(O)NR^(c8)R^(d8), NR^(c8)C(O)OR^(a8), C(═NR^(e8))NR^(c8)R^(d8),NR^(c8)C(═NR^(e8))NR^(c8)R^(d8), S(O)R^(b8), S(O)NR^(c8)R^(d8),S(O)₂R^(b8), NR^(c8)S(O)₂R^(b8), NR^(c8)S(O)₂NR^(c8)R^(d8), andS(O)₂NR^(c8)R^(d8), wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-6 membered heteroaryl areeach optionally substituted by 1, 2, or 3 substituents independentlyselected from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, CN,OR^(a8), SR^(a8), C(O)R^(b8), C(O)NR^(c8)R^(d8), C(O)OR^(a8),OC(O)R^(b8), OC(O)NR^(c8)R^(d8), NR^(c8)R^(d8), NR^(c8)C(O)R^(b8),NR^(c8)C(O)NR^(c8)R^(d8), NR^(c8)C(O)OR^(a8), C(═NR^(e8))NR^(c8)R^(d8),NR^(c8)C(═NR^(e8))NR^(c8)R^(d8), S(O)R^(b8), S(O)NR^(c8)R^(d8),S(O)₂R^(b8), NR^(c8)S(O)₂R^(b8), NR^(c8)S(O)₂NR^(c8)R^(d8), andS(O)₂NR^(c8)R^(d8);

each R^(a6), R^(b6), R^(c6), and R^(d6) is independently selected fromH, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl, whereinsaid C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are each optionallysubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, halo, CN, OR^(a8),SR^(a8), C(O)R^(b8), C(O)NR^(c8)R^(d8), C(O)OR^(a8), OC(O)R^(b8),OC(O)NR^(c8)R^(d8), NR^(c8)R^(d8), NR^(c8)C(O)R^(b8),NR^(c8)C(O)NR^(c8)R^(d8), NR^(c8)C(O)OR^(a8), C(═NR^(e8))NR^(c8)R^(d8),NR^(c8)C(═NR^(e8))NR^(c8)R^(d8), S(O)R^(b8), S(O)NR^(c8)R^(d8),S(O)₂R^(b8), NR^(c8)S(O)₂R^(b8), NR^(c8)S(O)₂NR^(c8)R^(d8), andS(O)₂NR^(c8)R^(d8);

or any R^(c6) and R^(d6) together with the N atom to which they areattached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, or 3 substituents independentlyselected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo, CN, OR^(a8), SR^(a8),C(O)R^(b8), C(O)NR^(c8)R^(d8), C(O)OR^(a8), OC(O)R^(b8),OC(O)NR^(c8)R^(d8), NR^(c8)R^(d8), NR^(c8)C(O)R^(b8),NR^(c8)C(O)NR^(c8)R^(d8), NR^(c8)C(O)OR^(a8), C(═NR^(e8))NR^(c8)R^(d8),NR^(c8)C(═NR^(e8))NR^(c8)R^(d8), S(O)R^(b8), S(O)NR^(c8)R^(d8),S(O)₂R^(b8), NR^(c8)S(O)₂R^(b8), NR^(c8)S(O)₂NR^(c8)R^(d8), andS(O)₂NR^(c8)R^(d8);

each R^(a7), R^(b7), R^(c7), and R^(d7) is independently selected fromH, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are each optionallysubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, halo, CN, OR^(a8),SR^(a8), C(O)R^(b8), C(O)NR^(c8)R^(d8), C(O)OR^(a8), OC(O)R^(b8),OC(O)NR^(c8)R^(d8), NR^(c8)R^(d8), NR^(c8)C(O)R^(b8),NR^(c8)C(O)NR^(c8)R^(d8), NR^(c8)C(O)OR^(a8), C(═NR^(e8))NR^(c8)R^(d8),NR^(c8)C(═NR^(e8))NR^(c8)R^(d8), S(O)R^(b8), S(O)NR^(c8)R^(d8),S(O)₂R^(b8), NR^(c8)S(O)₂R^(b8), NR^(c8)S(O)₂NR^(c8)R^(d8), andS(O)₂NR^(c8)R^(d8);

or any R^(c7) and R^(d7) together with the N atom to which they areattached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, or 3 substituents independentlyselected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₁₋₆ haloalkyl,halo, CN, OR^(a8), SR^(a8), C(O)R^(b8), C(O)NR^(c8)R^(d8), C(O)OR^(a8),OC(O)R^(b8), OC(O)NR^(c8)R^(d8), NR^(c8)R^(d8), NR^(c8)C(O)R^(b8),NR^(c8)C(O)NR^(c8)R^(d8), NR^(c8)C(O)OR^(a8), C(═NR^(e8))NR^(c8)R^(d8),NR^(c8)C(═NR^(e8))NR^(c8)R^(d8), S(O)R^(b8), S(O)NR^(c8)R^(d8),S(O)₂R^(b8), NR^(c8)S(O)₂R^(b8), NR^(c8)S(O)₂NR^(c8)R^(d8), andS(O)₂NR^(c8)R^(d8), wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-6 membered heteroaryl areeach optionally substituted by 1, 2, or 3 substituents independentlyselected from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, CN,OR^(a8), SR^(a8), C(O)R^(b8), C(O)NR^(c8)R^(d8), C(O)OR^(a8),OC(O)R^(b8), OC(O)NR^(c8)R^(d8), NR^(c8)R^(d8), NR^(c8)C(O)R^(b8),NR^(c8)C(O)NR^(c8)R^(d8), NR^(c8)C(O)OR^(a8), C(═NR^(e8))NR^(c8)R^(d8),NR^(c8)C(═NR^(e8))NR^(c8)R^(d8), S(O)R^(b8), S(O)NR^(c8)R^(d8),S(O)₂R^(b8), NR^(c8)S(O)₂R^(b8), NR^(c8)S(O)₂NR^(c8)R^(d8), andS(O)₂NR^(c8)R^(d8);

each R^(a8), R^(b8), R^(e8), and R^(d8) is independently selected fromH, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl, whereinsaid C₁₋₄ alkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl are each optionallysubstituted with 1, 2, or 3 substituents independently selected from OH,CN, amino, halo, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄alkylamino, di(C₁₋₄ alkyl)amino, C₁₋₄ haloalkyl, and C₁₋₄ haloalkoxy;and

each R^(e1), R^(e2), R^(e3), R^(e4), R^(e5), R^(e6), R^(e7), and R^(e8)is independently selected from H, C₁₋₄ alkyl, and CN;

wherein when X is N; then Ring A is substituted by at least one R^(A) orRing B is substituted by at least one R^(B).

In some embodiments:

X is N or CR^(X);

Y is (a) C═O and Z is NR^(Z) or (b) Y is CR³ and Z is N;

wherein the bond between Y and Z represented by

is a single bond in the case of (a) and a double bond in the case of(b);

Ring A is C₆₋₁₀ aryl optionally substituted by 1, 2, 3, or 4substituents independently selected from R^(A);

Ring B is C₆₋₁₀ aryl optionally substituted by 1, 2, 3, or 4substituents independently selected from R^(B);

R¹ is halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, Cy¹,CN, OR^(a1), SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1),OC(O)R^(b1), OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1), C(═NR^(e1))R^(b1),C(═NR^(e1))NR^(c1)R^(d1), NR^(c1)C(═NR^(e1))NR^(c1)R^(d1),NR^(c1)S(O)R^(b1), NR^(c1)S(O)₂R^(b1), NR^(c1)S(O)₂NR^(c1)R^(d1),S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1), or S(O)₂NR^(c1)R^(d1),wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are eachoptionally substituted with 1, 2, or 3 substituents independentlyselected from Cy¹, halo, CN, OR^(a1), SR^(a1), C(O)R^(b1),C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1), OC(O)NR^(c1)R^(d1),NR^(c1)R^(d1), N^(c1)C(O)R^(b1), NR^(c1)C(O)OR^(a1),NR^(c1)C(O)NR^(c1)R^(d1), C(═NR^(e1))R^(b1), C(═NR^(e1))NR^(c1)R^(d1),NR^(c1)C(═NR^(e1))NR^(c1)R^(d1), NR^(c1)S(O)R^(b1), NR^(c1)S(O)₂R^(b1),NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1),and S(O)₂NR^(c1)R^(d1);

R³ is H;

each R^(A) is independently selected from halo, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, CN, NO₂, OR^(a4), C(O)R^(b4),C(O)NR^(c4)R^(d4), C(O)OR^(a4), NR^(c4)R^(d4) NR^(c4)C(O)R^(b4),S(O)₂R^(b4), and S(O)₂NR^(c4)R^(d4), wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, and C₂₋₆ alkynyl are each optionally substituted by 1, 2, or 3,substituents independently selected from halo, C₁₋₆ haloalkyl, CN, NO₂,OR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4), NR^(c4)R^(d4)NR^(c4)C(O)R^(b4), S(O)₂R^(b4), and S(O)₂NR^(c4)R^(d4);

each R^(B) is independently selected from halo, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, CN, NO₂, OR^(a5), C(O)R^(b5),C(O)NR^(c5)R^(d5), C(O)OR^(a5), NR^(c5)R^(d5), NR^(c5)C(O)R^(b5),S(O)₂R^(b5), and S(O)₂NR^(c5)R^(d5), wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, and C₂₋₆ alkynyl are each optionally substituted by 1, 2, or 3substituents independently selected from halo, C₁₋₆ haloalkyl, CN, NO₂,OR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5), NR^(c5)R^(d5),NR^(c5)C(O)R^(b5), S(O)₂R^(b5), and S(O)₂NR^(c5)R^(d5);

R^(X) is H;

R^(Z) is H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, orCy⁴, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are eachoptionally substituted with 1, 2, 3, 4, or 5 substituents independentlyselected from Cy⁴, halo, CN, OR^(a3), SR^(a3), C(O)R^(b3),C(O)NR^(c3)R^(d3), C(O)OR^(a3), OC(O)R^(b3), OC(O)NR^(c3)R^(d3),NR^(c3)R^(d3), NR^(c3)C(O)R^(b3), NR^(c3)C(O)OR^(a3),NR^(c3)C(O)NR^(c3)R^(d3), C(═NR^(e3))R^(b3), C(═NR^(e3))NR^(c3)R^(d3),NR^(c3)C(═NR^(e3))NR^(c3)R^(d3), NR^(c3)S(O)R^(b3), NR^(c3)S(O)₂R^(b3),NR^(c3) S(O)₂NR^(c3)R^(d3), S(O)R^(b3), S(O)NR^(c3)R^(d3), S(O)₂R^(b3),and S(O)₂NR^(c3)R^(d3);

each Cy¹, Cy⁴, and Cy⁵ is independently selected from C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, and 4-10 memberedheterocycloalkyl, each of which is optionally substituted with 1, 2, 3,or 4 substituents independently selected from R^(Cy);

each R^(Cy) is selected from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄cyanoalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₄ alkyl-,C₃₋₇ cycloalkyl-C₁₋₄ alkyl-, (5-6 membered heteroaryl)-C₁₋₄ alkyl-, (4-7membered heterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a6), SR^(a6),C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6), OC(O)R^(b6),OC(O)NR^(c6)R^(d6), C(═NR^(e6))NR^(c6)R^(d6),NR^(c6)C(═NR^(e6))NR^(c6)R^(d6), NR^(c6)R^(d6), NR^(c6)C(O)R^(b6),NR^(c6)C(O)OR^(a6), NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)S(O)R^(b6),NR^(c6)S(O)₂R^(b6), NR^(c6)S(O)₂NR^(c6)R^(d6), S(O)R^(b6),S(O)NR^(c6)R^(d6), S(O)₂R^(b6), and S(O)₂NR^(c6)R^(d6), wherein saidC₁₋₄ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₄ alkyl-,C₃₋₇ cycloalkyl-C₁₋₄ alkyl-, (5-6 membered heteroaryl)-C₁₋₄ alkyl-, and(4-7 membered heterocycloalkyl)-C₁₋₄ alkyl- are each optionallysubstituted by 1, 2, or 3 substituents independently selected from C₁₋₄alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, halo, CN, NO₂, OR^(a6), SR^(a6),C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6), OC(O)R^(b6),OC(O)NR^(c6)R^(d6), C(═NR^(e6))NR^(c6)R^(d6),NR^(c6)C(═NR^(e6))NR^(c6)R^(d6), NR^(c6)R^(d6), NR^(c6)C(O)R^(b6),NR^(c6)C(O)OR^(a6), NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)S(O)R^(b6),NR^(c6)S(O)₂R^(b6), NR^(c6)S(O)₂NR^(c6)R^(d6),S(O)R^(b6)S(O)NR^(c6)R^(d6), S(O)₂R^(b6), and S(O)₂NR^(c6)R^(d6);

each R^(a1) is independently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, and Cy⁵, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl are each optionally substituted with 1, 2, or 3 substituentsindependently selected from Cy⁵, halo, CN, OR^(a7), SR^(a7), C(O)R^(b7),C(O)NR^(c7)R^(d7), C(O)OR^(a7), OC(O)R^(b7), OC(O)NR^(c7)R^(d7),NR^(c7)R^(d7), NR^(c7)C(O)R^(b7), NR^(c7)C(O)OR^(a7),NR^(c7)C(O)NR^(c7)R^(d7), C(═NR^(e7))R^(b7), C(═NR^(e7))NR^(c7)R^(d7),NR^(c7)C(═NR^(e7))NR^(c7)R^(d7), NR^(c7)S(O)R^(b7), NR^(c7)S(O)₂R^(b7),NR^(c7)S(O)₂NR^(c7)R^(d7), S(O)R^(b7), S(O)NR^(c7)R^(d7), S(O)₂R^(b7),and S(O)₂NR^(c7)R^(d7);

each R^(b1), R^(c1), and R^(d1) is independently selected from H, C₁₋₆alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄alkyl-, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- are each optionally substituted with 1, 2,3, 4, or 5 substituents independently selected from C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄ cyanoalkyl, halo, CN, OR^(a8), SR^(a8), C(O)R^(b8),C(O)NR^(c8)R^(d8), C(O)OR^(a8), OC(O)R^(b8), OC(O)NR^(c8)R^(d8),NR^(c8)R^(d8), NR^(c8)C(O)R^(b8), NR^(c8)C(O)NR^(c8)R^(d8),NR^(c8)C(O)OR^(a8), C(═NR^(e8))NR^(c8)R^(d8),NR^(c8)C(═NR^(e8))NR^(c8)R^(d8), S(O)R^(b8), S(O)NR^(c8)R^(d8),S(O)₂R^(b8), NR^(c8)S(O)₂R^(b8), NR^(c8)S(O)₂NR^(c8)R^(d8), andS(O)₂NR^(c8)R^(d8);

or any R^(c1) and R^(d1) together with the N atom to which they areattached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, or 3 substituents independentlyselected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₁₋₆ haloalkyl,halo, CN, OR^(a8), SR^(a8), C(O)R^(b8), C(O)NR^(c8)R^(d8), C(O)OR^(a8),OC(O)R^(b8), OC(O)NR^(c8)R^(d8), NR^(c8)R^(d8), NR^(c8)C(O)R^(b8),NR^(c8)C(O)NR^(c8)R^(d8), NR^(c8)C(O)OR^(a8), C(═NR^(e8))NR^(c8)R^(d8),NR^(c8)C(═NR^(e8))NR^(c8)R^(d8), S(O)R^(b8), S(O)NR^(c8)R^(d8),S(O)₂R^(b8), NR^(c8)S(O)₂R^(b8), NR^(c8)S(O)₂NR^(c8)R^(d8), andS(O)₂NR^(c8)R^(d8), wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-6 membered heteroaryl areeach optionally substituted by 1, 2, or 3 substituents independentlyselected from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, CN,OR^(a8), SR^(a8), C(O)R^(b8), C(O)NR^(c8)R^(d8), C(O)OR^(a8),OC(O)R^(b8), OC(O)NR^(c8)R^(d8), NR^(c8)R^(d8), NR^(c8)C(O)R^(b8),NR^(c8)C(O)NR^(c8)R^(d8), NR^(c8)C(O)OR^(a8), C(═NR^(e8))NR^(c8)R^(d8),NR^(c8)C(═NR^(e8))NR^(c8)R^(d8), S(O)R^(b8), S(O)NR^(c8)R^(d8),S(O)₂R^(b8), NR^(c8)S(O)₂R^(b8), NR^(c8)S(O)₂NR^(c8)R^(d8), andS(O)₂NR^(c8)R^(d8);

each R^(a3), R^(b3), R^(c3), and R^(d3), is independently selected fromH, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are each optionallysubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, halo, CN, OR^(a8),SR^(a8), C(O)R^(b8), C(O)NR^(c8)R^(d8), C(O)OR^(a8), OC(O)R^(b8),OC(O)NR^(c8)R^(d8), NR^(c8)R^(d8), NR^(c8)C(O)R^(b8),NR^(c8)C(O)NR^(c8)R^(d8), NR^(c8)C(O)OR^(a8), C(═NR^(e8))NR^(c8)R^(d8),NR^(c8)C(═NR^(e8))NR^(c8)R^(d8), S(O)R^(b8), S(O)NR^(c8)R^(d8),S(O)₂R^(b8), NR^(c8)S(O)₂R^(b8), NR^(c8)S(O)₂NR^(c8)R^(d8), andS(O)₂NR^(c8)R^(d8);

or any R^(c3) and R^(d3), together with the N atom to which they areattached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, or 3 substituents independentlyselected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo, CN, OR^(a8), SR^(a8),C(O)R^(b8), C(O)NR^(c8)R^(d8), C(O)OR^(a8), OC(O)R^(b8),OC(O)NR^(c8)R^(d8), NR^(c8)R^(d8), NR^(c8)C(O)R^(b8),NR^(c8)C(O)NR^(c8)R^(d8), NR^(c8)C(O)OR^(a8), C(═NR^(e8))NR^(c8)R^(d8),NR^(c8)C(═NR^(e8))NR^(c8)R^(d8), S(O)R^(b8), S(O)NR^(c8)R^(d8),S(O)₂R^(b8), NR^(c8)S(O)₂R^(b8), NR^(c8)S(O)₂NR^(c8)R^(d8), andS(O)₂NR^(c8)R^(d8);

each R^(a4), R^(b4), R^(c4), and R^(d4) is independently selected fromH, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl, whereinsaid C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are each optionallysubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, halo, CN, OR^(a8),SR^(a8), C(O)R^(b8), C(O)NR^(c8)R^(d8), C(O)OR^(a8), OC(O)R^(b8),OC(O)NR^(c8)R^(d8), NR^(c8)R^(d8), NR^(c8)C(O)R^(b8),NR^(c8)C(O)NR^(c8)R^(d8), NR^(c8)C(O)OR^(a8), C(═NR^(e8))NR^(c8)R^(d8),NR^(c8)C(═NR^(e8))NR^(c8)R^(d8), S(O)R^(b8), S(O)NR^(c8)R^(d8),S(O)₂R^(b8), NR^(c8)S(O)₂R^(b8), NR^(c8)S(O)₂NR^(c8)R^(d8), andS(O)₂NR^(c5)R^(d5);

or any R^(c4) and R^(d4) together with the N atom to which they areattached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, or 3 substituents independentlyselected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo, CN, OR^(a8), SR^(a8),C(O)R^(b8), C(O)NR^(c8)R^(d8), C(O)OR^(a8), OC(O)R^(b8),OC(O)NR^(c8)R^(d8), NR^(c8)R^(d8), NR^(c8)C(O)R^(b8),NR^(c8)C(O)NR^(c8)R^(d8), NR^(c8)C(O)OR^(a8), C(═NR^(e8))NR^(c8)R^(d8),NR^(c8)C(═NR^(e8))NR^(c8)R^(d8), S(O)R^(b8), S(O)NR^(c8)R^(d8),S(O)₂R^(b8), NR^(c8)S(O)₂R^(b8), NR^(c8)S(O)₂NR^(c8)R^(d8), andS(O)₂NR^(c8)R^(d8);

each R^(a5), R^(b5), R^(c5), and R^(d5) is independently selected fromH, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are each optionallysubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, halo, CN, OR^(a8),SR^(a8), C(O)R^(b8), C(O)NR^(c8)R^(d8), C(O)OR^(a8), OC(O)R^(b8),OC(O)NR^(c8)R^(d8), NR^(c8)R^(d8), NR^(c8)C(O)R^(b8),NR^(c8)C(O)NR^(c8)R^(d8), NR^(c8)C(O)OR^(a8), C(═NR^(e8))NR^(c8)R^(d8),NR^(c8)C(═NR^(e8))NR^(c8)R^(d8), S(O)R^(b8), S(O)NR^(c8)R^(d8),S(O)₂R^(b8), NR^(c8)S(O)₂R^(b8), NR^(c8)S(O)₂NR^(c8)R^(d8), andS(O)₂NR^(c8)R^(d8);

or any R^(c5) and R^(d5) together with the N atom to which they areattached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, or 3 substituents independentlyselected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₁₋₆ haloalkyl,halo, CN, OR^(a8), SR^(a8), C(O)R^(b8), C(O)NR^(c8)R^(d8), C(O)OR^(a8),OC(O)R^(b8), OC(O)NR^(c8)R^(d8), NR^(c8)R^(d8), NR^(c8)C(O)R^(b8),NR^(c8)C(O)NR^(c8)R^(d8), NR^(c8)C(O)OR^(a8), C(═NR^(e8))NR^(c8)R^(d8),NR^(c8)C(═NR^(e8))NR^(c8)R^(d8), S(O)R^(b8), S(O)NR^(c8)R^(d8),S(O)₂R^(b8), NR^(c8)S(O)₂R^(b8), NR^(c8)S(O)₂NR^(c8)R^(d8), andS(O)₂NR^(c8)R^(d8), wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-6 membered heteroaryl areeach optionally substituted by 1, 2, or 3 substituents independentlyselected from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, CN,OR^(a8), SR^(a8), C(O)R^(b8), C(O)NR^(c8)R^(d8), C(O)OR^(a8),OC(O)R^(b8), OC(O)NR^(c8)R^(d8), NR^(c8)R^(d8), NR^(c8)C(O)R^(b8),NR^(c8)C(O)NR^(c8)R^(d8), NR^(c8)C(O)OR^(a8), C(═NR^(e8))NR^(c8)R^(d8),NR^(c8)C(═NR^(e8))NR^(c8)R^(d8), S(O)R^(b8), S(O)NR^(c8)R^(d8),S(O)₂R^(b8), NR^(c8)S(O)₂R^(b8), NR^(c8)S(O)₂NR^(c8)R^(d8), andS(O)₂NR^(c8)R^(d8);

each R^(a6), R^(b6), R^(c6), and R^(d6) is independently selected fromH, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl, whereinsaid C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are each optionallysubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, halo, CN, OR^(a8),SR^(a8), C(O)R^(b8), C(O)NR^(c8)R^(d8), C(O)OR^(a8), OC(O)R^(b8),OC(O)NR^(c8)R^(d8), NR^(c8)R^(d8), NR^(c8)C(O)R^(b8),NR^(c8)C(O)NR^(c8)R^(d8), NR^(c8)C(O)OR^(a8), C(═NR^(e8))NR^(c8)R^(d8),NR^(c8)C(═NR^(e8))NR^(c8)R^(d8), S(O)R^(b8), S(O)NR^(c8)R^(d8),S(O)₂R^(b8), NR^(c8)S(O)₂R^(b8), NR^(c8)S(O)₂NR^(c8)R^(d8), andS(O)₂NR^(c8)R^(d8);

or any R^(c6) and R^(d6) together with the N atom to which they areattached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, or 3 substituents independentlyselected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo, CN, OR^(a8), SR^(a8),C(O)R^(b8), C(O)NR^(c8)R^(d8), C(O)OR^(a8), OC(O)R^(b8),OC(O)NR^(c8)R^(d8), NR^(c8)R^(d8), NR^(c8)C(O)R^(b8),NR^(c8)C(O)NR^(c8)R^(d8), NR^(c8)C(O)OR^(a8), C(═NR^(e8))NR^(c8)R^(d8),NR^(c5)C(═NR^(e8))NR^(c8)R^(d8), S(O)R^(b8), S(O)NR^(c8)R^(d8),S(O)₂R^(b8), NR^(c8)S(O)₂R^(b8), NR^(c8)S(O)₂NR^(c8)R^(d8), andS(O)₂NR^(c8)R^(d8);

each R^(a7), R^(b7), R^(c7), and R^(d7) is independently selected fromH, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are each optionallysubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, halo, CN, OR^(a8),SR^(a8), C(O)R^(b8), C(O)NR^(c8)R^(d8), C(O)OR^(a8), OC(O)R^(b8),OC(O)NR^(c8)R^(d8), NR^(c8)R^(d8), NR^(c8)C(O)R^(b8),NR^(c8)C(O)NR^(c8)R^(d8), NR^(c8)C(O)OR^(a8), C(═NR^(e8))NR^(c8)R^(d8),NR^(c8)C(═NR^(e8))NR^(c8)R^(d8), S(O)R^(b8), S(O)NR^(c8)R^(d8),S(O)₂R^(b8), NR^(c8)S(O)₂R^(b8), NR^(c8)S(O)₂NR^(c8)R^(d8), andS(O)₂NR^(c8)R^(d8);

or any R^(c7) and R^(d7) together with the N atom to which they areattached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, or 3 substituents independentlyselected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₁₋₆ haloalkyl,halo, CN, OR^(a8), SR^(a8), C(O)R^(b8), C(O)NR^(c8)R^(d8), C(O)OR^(a8),OC(O)R^(b8), OC(O)NR^(c8)R^(d8), NR^(c8)R^(d8), NR^(c8)C(O)R^(b8),NR^(c8)C(O)NR^(c8)R^(d8), NR^(c8)C(O)OR^(a8), C(═NR^(e8))NR^(c8)R^(d8),NR^(c8)C(═NR^(e8))NR^(c8)R^(d8), S(O)R^(b8), S(O)NR^(c8)R^(d8),S(O)₂R^(b8), NR^(c8)S(O)₂R^(b8), NR^(c8)S(O)₂NR^(c8)R^(d8), andS(O)₂NR^(c8)R^(d8), wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-6 membered heteroaryl areeach optionally substituted by 1, 2, or 3 substituents independentlyselected from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, CN,OR^(a8), SR^(a8), C(O)R^(b8), C(O)NR^(c8)R^(d8), C(O)OR^(a8),OC(O)R^(b8), OC(O)NR^(c8)R^(d8), NR^(c8)R^(d8), NR^(c8)C(O)R^(b8),NR^(c8)C(O)NR^(c8)R^(d8), NR^(c8)C(O)OR^(a8), C(═NR^(e8))NR^(c8)R^(d8),NR^(c8)C(═NR^(e8))NR^(c8)R^(d8), S(O)R^(b8), S(O)NR^(c8)R^(d8),S(O)₂R^(b8), NR^(c8)S(O)₂R^(b8), NR^(c8)S(O)₂NR^(c8)R^(d8), andS(O)₂NR^(c8)R^(d8);

each R^(a8), R^(b8), R^(c8), and R^(d8) is independently selected fromH, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl, whereinsaid C₁₋₄ alkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl are each optionallysubstituted with 1, 2, or 3 substituents independently selected from OH,CN, amino, halo, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄alkylamino, di(C₁₋₄ alkyl)amino, C₁₋₄ haloalkyl, and C₁₋₄ haloalkoxy;and

each R^(e1), R^(e3), R^(e6), R^(e7), and R^(e8) is independentlyselected from H, C₁₋₄ alkyl, and CN;

wherein when X is N; then Ring A is substituted by at least one R^(A) orRing B is substituted by at least one R^(B).

In some embodiments:

X is N or CR^(X);

Y is (a) C═O and Z is NR^(Z) or (b) Y is CR³ and Z is N;

wherein the bond between Y and Z represented by

is a single bond in the case of (a) and a double bond in the case of(b);

Ring A is phenyl optionally substituted by 1 or 2 substituentsindependently selected from R^(A);

Ring B is phenyl optionally substituted by 1 or 2 substituentsindependently selected from RB;

R¹ is OR^(a1);

R³ is H;

each R^(A) is independently selected from halo, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, CN, NO₂, OR^(a4), C(O)R^(b4),C(O)NR^(c4)R^(d4), C(O)OR^(a4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),S(O)₂R^(b4), and S(O)₂NR^(c4)R^(d4), wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, and C₂₋₆ alkynyl are each optionally substituted by 1, 2, or 3,substituents independently selected from halo, C₁₋₆ haloalkyl, CN, NO₂,OR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4), NR^(c4)R^(d4)NR^(c4)C(O)R^(b4), S(O)₂R^(b4), and S(O)₂NR^(c4)R^(d4);

each R^(B) is independently selected from halo, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, CN, NO₂, OR^(a5), C(O)R^(b5),C(O)NR^(c5)R^(d5), C(O)OR^(a5), NR^(c5)R^(d5), NR^(c5)C(O)R^(b5),S(O)₂R^(b5), and S(O)₂NR^(c5)R^(d5), wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, and C₂₋₆ alkynyl are each optionally substituted by 1, 2, or 3substituents independently selected from halo, C₁₋₆ haloalkyl, CN, NO₂,OR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5), NR^(c5)R^(d5),NR^(c5)C(O)R^(b5), S(O)₂R^(b5), and S(O)₂NR^(c5)R^(d5);

R^(X) is H;

R^(Z) is H, C₁₋₆ alkyl, or C₁₋₆ haloalkyl, wherein said C₁₋₆ alkyl isoptionally substituted with 1, 2, 3, 4, or 5 substituents independentlyselected from Cy⁴, halo, CN, OR^(a3), C(O)NR^(c3)R^(d3), andNR^(c3)R^(d3);

each Cy⁴ is independently selected from phenyl, C₃₋₇ cycloalkyl, 5-6membered heteroaryl, and 4-7 membered heterocycloalkyl, each of which isoptionally substituted with 1 or 2 substituents independently selectedfrom R^(Cy);

each Cy⁵ is independently selected from 4-7 membered heterocycloalkyl,each of which is optionally substituted with 1 or 2 substituentsindependently selected from R^(Cy);

each R^(Cy) is selected from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄cyanoalkyl, CN, NO₂, OR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6),C(O)OR^(a6), NR^(c6)R^(d6), NR^(c6)C(O)R^(b6), S(O)₂R^(b6), andS(O)₂NR^(c6)R^(d6);

each R^(a1) is C₁₋₆ alkyl optionally substituted with Cy⁵;

each R^(a3), R³, and R^(d3), is independently selected from H, C₁₋₆alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄alkyl-, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- are each optionally substituted with 1, 2,3, 4, or 5 substituents independently selected from C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄ cyanoalkyl, halo, CN, OR^(a8), SR^(a8), C(O)R^(b8),C(O)NR^(c8)R^(d8), C(O)OR^(a8), OC(O)R^(b8), OC(O)NR^(c8)R^(d8),NR^(c8)R^(d8), NR^(c8)C(O)R^(b8), NR^(c8)C(O)NR^(c8)R^(d8),NR^(c8)C(O)OR^(a8), C(═NR^(e8))NR^(c8)R^(d8),NR^(c8)C(═NR^(e8))NR^(c8)R^(d8), S(O)R^(b8), S(O)NR^(c8)R^(d8),S(O)₂R^(b8), NR^(c8)S(O)₂R^(b8), NR^(c8)S(O)₂NR^(c8)R^(d8), andS(O)₂NR^(c8)R^(d8);

or any R^(c3) and R^(d3), together with the N atom to which they areattached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, or 3 substituents independentlyselected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo, CN, OR^(a8), SR^(a8),C(O)R^(b8), C(O)NR^(c8)R^(d8), C(O)OR^(a8), OC(O)R^(b8),OC(O)NR^(c8)R^(d8), NR^(c8)R^(d8), NR^(c8)C(O)R^(b8),NR^(c8)C(O)NR^(c8)R^(d8), NR^(c8)C(O)OR^(a8), C(═NR^(e8))NR^(c8)R^(d8),NR^(c8)C(═NR^(e8))NR^(c8)R^(d8), S(O)R^(b8), S(O)NR^(c8)R^(d8),S(O)₂R^(b8), NR^(c8)S(O)₂R^(b8), NR^(c8)S(O)₂NR^(c8)R^(d8), andS(O)₂NR^(c8)R^(d8);

each R^(a4), R^(b4), R^(c4), and R^(d4) is independently selected fromH, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl, whereinsaid C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are each optionallysubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, halo, CN, OR^(a8),SR^(a8), C(O)R^(b8), C(O)NR^(c8)R^(d8), C(O)OR^(a8), OC(O)R^(b8),OC(O)NR^(c8)R^(d8), NR^(c8)R^(d8), NR^(c8)C(O)R^(b8),NR^(c8)C(O)NR^(c8)R^(d8), NR^(c8)C(O)OR^(a8), C(═NR^(e8))NR^(c8)R^(d8),NR^(c8)C(═NR^(e8))NR^(c8)R^(d8), S(O)R^(b8), S(O)NR^(c8)R^(d8),S(O)₂R^(b8), NR^(c8)S(O)₂R^(b8), NR^(c5)S(O)₂NR^(c8)R^(d8), andS(O)₂NR^(c8)R^(d8);

or any R^(c4) and R^(d4) together with the N atom to which they areattached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, or 3 substituents independentlyselected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo, CN, OR^(a8), SR^(a8),C(O)R^(b8), C(O)NR^(c8)R^(d8), C(O)OR^(a8), OC(O)R^(b8),OC(O)NR^(c8)R^(d8), NR^(c8)R^(d8), NR^(c8)C(O)R^(b8),NR^(c8)C(O)NR^(c8)R^(d8), NR^(c8)C(O)OR^(a8), C(═NR^(e8))NR^(c8)R^(d8),NR^(c8)C(═NR^(e8))NR^(c8)R^(d8), S(O)R^(b8), S(O)NR^(c8)R^(d8),S(O)₂R^(b8), NR^(c8)S(O)₂R^(b8), NR^(c8)S(O)₂NR^(c8)R^(d8), andS(O)₂NR^(c8)R^(d8);

each R^(a5), R^(b5), R^(c5), and R^(d5) is independently selected fromH, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are each optionallysubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, halo, CN, OR^(a8),SR^(a8), C(O)R^(b8), C(O)NR^(c8)R^(d8), C(O)OR^(a8), OC(O)R^(b8),OC(O)NR^(c8)R^(d8), NR^(c8)R^(d8), NR^(c8)C(O)R^(b8),NR^(c8)C(O)NR^(c8)R^(d8), NR^(c8)C(O)OR^(a8), C(═NR^(e8))NR^(c8)R^(d8),NR^(c8)C(═NR^(e8))NR^(c8)R^(d8), S(O)R^(b8), S(O)NR^(c8)R^(d8),S(O)₂R^(b8), NR^(c8)S(O)₂R^(b8), NR^(c8)S(O)₂NR^(c8)R^(d8), andS(O)₂NR^(c8)R^(d8);

or any R^(c5) and R^(d5) together with the N atom to which they areattached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, or 3 substituents independentlyselected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₁₋₆ haloalkyl,halo, CN, OR^(a8), SR^(a8), C(O)R^(b8), C(O)NR^(c8)R^(d8), C(O)OR^(a8),OC(O)R^(b8), OC(O)NR^(c8)R^(d8), NR^(c8)R^(d8), NR^(c8)C(O)R^(b8),NR^(c8)C(O)NR^(c8)R^(d8), NR^(c8)C(O)OR^(a8), C(═NR^(e8))NR^(c8)R^(d8),NR^(c8)C(═NR^(e8))NR^(c8)R^(d8), S(O)R^(b8), S(O)NR^(c8)R^(d8),S(O)₂R^(b8), NR^(c8)S(O)₂R^(b8), NR^(c8)S(O)₂NR^(c8)R^(d8), andS(O)₂NR^(c8)R^(d8), wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-6 membered heteroaryl areeach optionally substituted by 1, 2, or 3 substituents independentlyselected from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, CN,OR^(a8), SR^(a8), C(O)R^(b8), C(O)NR^(c8)R^(d8), C(O)OR^(a8),OC(O)R^(b8), OC(O)NR^(c8)R^(d8), NR^(c8)R^(d8), NR^(c8)C(O)R^(b8),NR^(c8)C(O)NR^(c8)R^(d8), NR^(c8)C(O)OR^(a8), C(═NR^(e8))NR^(c8)R^(d8),NR^(c8)C(═NR^(e8))NR^(c8)R^(d8), S(O)R^(b8), S(O)NR^(c8)R^(d8),S(O)₂R^(b8), NR^(c8)S(O)₂R^(b8), NR^(c8)S(O)₂NR^(c8)R^(d8), andS(O)₂NR^(c8)R^(d8);

each R^(a6), R^(b6), R^(c6), and R^(d6) is independently selected fromH, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl, whereinsaid C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are each optionallysubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, halo, CN, OR^(a8),SR^(a8), C(O)R^(b8), C(O)NR^(c8)R^(d8), C(O)OR^(a8), OC(O)R^(b8),OC(O)NR^(c8)R^(d8), NR^(c8)R^(d8), NR^(c8)C(O)R^(b8),NR^(c8)C(O)NR^(c8)R^(d8), NR^(c8)C(O)OR^(a8), C(═NR^(e8))NR^(c8)R^(d8),NR^(c8)C(═NR^(e8))NR^(c8)R^(d8), S(O)R^(b8), S(O)NR^(c8)R^(d8),S(O)₂R^(b8), NR^(c8)S(O)₂R^(b8), NR^(c8)S(O)₂NR^(c8)R^(d8), andS(O)₂NR^(c8)R^(d8);

or any R^(c6) and R^(d6) together with the N atom to which they areattached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, or 3 substituents independentlyselected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo, CN, OR^(a8), SR^(a8),C(O)R^(b8), C(O)NR^(c8)R^(d8), C(O)OR^(a8), OC(O)R^(b8),OC(O)NR^(c8)R^(d8), NR^(c8)R^(d8), NR^(c8)C(O)R^(b8),NR^(c8)C(O)NR^(c8)R^(d8), NR^(c8)C(O)OR^(a8), C(═NR^(e8))NR^(c8)R^(d8),NR^(c8)C(═NR^(e8))NR^(c8)R^(d8), S(O)R^(b5), S(O)NR^(c8)R^(d8),S(O)₂R^(b8), NR^(c8)S(O)₂R^(b8), NR^(c8)S(O)₂NR^(c8)R^(d8), andS(O)₂NR^(c8)R^(d8);

each R^(a8), R^(b5), R^(c8), and R^(d8) is independently selected fromH, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl, whereinsaid C₁₋₄ alkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl are each optionallysubstituted with 1, 2, or 3 substituents independently selected from OH,CN, amino, halo, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄alkylamino, di(C₁₋₄ alkyl)amino, C₁₋₄ haloalkyl, and C₁₋₄ haloalkoxy;and

each R^(e8) is independently selected from H, C₁₋₄ alkyl, and CN;

wherein when X is N; then Ring A is substituted by at least one R^(A) orRing B is substituted by at least one R^(B).

In some embodiments, X is N.

In some embodiments, X is CR^(X).

In some embodiments, Y is C═O and Z is NR^(Z).

In some embodiments, Y is CR³ and Z is N.

In some embodiments, Ring A is C₆₋₁₀ aryl optionally substituted by 1,2, 3, or 4 substituents independently selected from R^(A).

In some embodiments, Ring A is phenyl optionally substituted by 1 or 2substituents independently selected from R^(A).

In some embodiments, Ring A is phenyl substituted by CN.

In some embodiments, Ring B is C₆₋₁₀ aryl optionally substituted by 1,2, 3, or 4 substituents independently selected from R^(B).

In some embodiments, Ring B is phenyl optionally substituted by 1 or 2substituents independently selected from R^(B).

In some embodiments, Ring B is phenyl substituted by methyl.

In some embodiments, R³ is H.

In some embodiments, R^(Z) is H, C₁₋₆ alkyl, or C₁₋₆ haloalkyl, whereinsaid C₁₋₆ alkyl is optionally substituted with 1, 2, 3, 4, or 5substituents independently selected from Cy⁴, halo, CN, OR^(a3),C(O)NR^(c3)R^(d3), and NR^(c3)R^(d3).

In some embodiments, R^(Z) is H, C₁₋₄ alkyl, or C₁₋₆ haloalkyl, whereinsaid C₁₋₄ alkyl is optionally substituted with 1, 2, 3, 4, or 5substituents independently selected from OH, CN, F, phenyl, C₃₋₇cyclalkyl, 5-6 membered heterocycloalkyl, 5-6 membered heteroaryl,C(O)NH₂, phenoxy, and dimethylamino, wherein said phenyl is optionallysubstituted by CN and said pyrazolyl is optionally substituted bymethyl.

In some embodiments, R^(Z) is H, methyl, cyanomethyl, cyanoethyl,cyclopentylmethyl, tetrahydrofuranylmethyl,(1-methyl-1H-pyrazol-3-yl)methyl, morpholinylethyl, aminocarbonylmethyl,3,3,3-trifluoro-2-hydroxypropyl, piperidinylmethyl, phenoxyethyl,dimethylaminoethyl, benzyl, cyanophenyl, or hydroxyethyl.

In some embodiments, R^(X) is H.

In some embodiments, each R^(A) is independently selected from halo,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, CN, NO₂,OR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4), NR^(c4)R^(d4),NR^(c4)C(O)R^(b4), S(O)₂R^(b4), and S(O)₂NR^(c4)R^(d4), wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are each optionallysubstituted by 1, 2, or 3, substituents independently selected fromhalo, C₁₋₆ haloalkyl, CN, NO₂, OR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4),C(O)OR^(a4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4), S(O)₂R^(b4), andS(O)₂NR^(c4)R^(d4).

In some embodiments, R^(A) is CN.

In some embodiments, each RB is independently selected from halo, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, CN, NO₂, OR^(a5),C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5), NR^(c5)R^(d5),NR^(c5)C(O)R^(b5), S(O)₂R^(b5), and S(O)₂NR^(c5)R^(d5), wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are each optionallysubstituted by 1, 2, or 3 substituents independently selected from halo,C₁₋₆ haloalkyl, CN, NO₂, OR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5),C(O)OR^(a5), NR^(c5)R^(d5), NR^(c5)C(O)R^(b5)S(O)₂R^(b5), andS(O)₂NR^(c5)R^(d5).

In some embodiments, R^(B) is C₁₋₆ alkyl.

In some embodiments, R^(B) is methyl.

In some embodiments, each R^(a1) is C₁₋₆ alkyl optionally substitutedwith Cy⁵.

In some embodiments, each R^(a1) is C₁₋₆ alkyl optionally substitutedwith 4-7 membered heterocycloalkyl.

In some embodiments, each R^(a1) is pyrrolidinylmethyl.

In some embodiments, each Cy⁴ is phenyl, C₃₋₇ cycloalkyl, 5-6 memberedheteroaryl, and 5-6 membered heterocycloalkyl, each optionallysubstituted by one substituent independently selected from R^(Cy).

In some embodiments, each Cy⁴ is phenyl, cyclopentyl, tetrahydrofuranyl,pyrazolyl, morpholinyl, or piperidinyl, each optionally substituted byone substituent independently selected from methyl and CN.

In some embodiments, Cy⁵ is 4-7 heterocycloalkyl.

In some embodiments, Cy⁵ is pyrrolidinyl.

In some embodiments, the compounds of the invention have Formula IIa:

In some embodiments, the compounds of the invention have Formula IIb:

In some embodiments, the compounds of the invention have Formula IIIa orIIIb:

In some embodiments, the compounds of the invention have Formula IIIc orIIId:

In some embodiments, the compounds of the invention have Formula IVa:

wherein:

n is 0, 1, 2, 3, or 4; and

m is 0, 1, 2, 3, or 4.

In some embodiments, the compounds of the invention have Formula IVb:

wherein:

n is 0, 1, 2, 3, or 4; and

m is 0, 1, 2, 3, or 4.

In some embodiments, the compounds of the invention have Formula V:

In some embodiments, n is 0, 1, or 2.

In some embodiments, n is 1.

In some embodiments, m is 0, 1, or 2.

In some embodiments, m is 1.

It is appreciated that certain features of the invention, which are, forclarity, described in the context of separate embodiments, can also beprovided in combination in a single embodiment. Conversely, variousfeatures of the invention which are, for brevity, described in thecontext of a single embodiment, can also be provided separately or inany suitable subcombination.

As used herein, the phrase “optionally substituted” means unsubstitutedor substituted. As used herein, the term “substituted” means that ahydrogen atom is removed and replaced by a monovalent substituent, ortwo hydrogen atoms are replaced with a divalent substituent like aterminal oxo group. It is to be understood that substitution at a givenatom is limited by valency.

Throughout the definitions, the term “C_(i-j)” indicates a range whichincludes the endpoints, wherein i and j are integers and indicate thenumber of carbons. Examples include C₁₋₄, C₁₋₆, and the like.

The term “z-membered” (where z is an integer) typically describes thenumber of ring-forming atoms in a moiety where the number ofring-forming atoms is z. For example, piperidinyl is an example of a6-membered heterocycloalkyl ring, pyrazolyl is an example of a5-membered heteroaryl ring, pyridyl is an example of a 6-memberedheteroaryl ring, and 1, 2, 3, 4-tetrahydro-naphthalene is an example ofa 10-membered cycloalkyl group.

As used herein, the term “C_(i-j) alkyl,” employed alone or incombination with other terms, refers to a saturated hydrocarbon groupthat may be straight-chain or branched, having i to j carbons. In someembodiments, the alkyl group contains from 1 to 6 carbon atoms or from 1to 4 carbon atoms, or from 1 to 3 carbon atoms. Examples of alkylmoieties include, but are not limited to, chemical groups such asmethyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, and t-butyl.

As used herein, the term “C_(i-j) alkoxy,” employed alone or incombination with other terms, refers to a group of formula —O-alkyl,wherein the alkyl group has i to j carbons. Example alkoxy groupsinclude methoxy, ethoxy, and propoxy (e.g., n-propoxy and isopropoxy).In some embodiments, the alkyl group has 1 to 3 carbon atoms.

As used herein, “C_(i-j) alkenyl,” employed alone or in combination withother terms, refers to an unsaturated hydrocarbon group having one ormore double carbon-carbon bonds and having i to j carbons. In someembodiments, the alkenyl moiety contains 2 to 6 or 2 to 4 carbon atoms.Example alkenyl groups include, but are not limited to, ethenyl,n-propenyl, isopropenyl, n-butenyl, sec-butenyl, and the like.

As used herein, “C_(i-j) alkynyl,” employed alone or in combination withother terms, refers to an unsaturated hydrocarbon group having one ormore triple carbon-carbon bonds and having i to j carbons. Examplealkynyl groups include, but are not limited to, ethynyl, propyn-1-yl,propyn-2-yl, and the like. In some embodiments, the alkynyl moietycontains 2 to 6 or 2 to 4 carbon atoms.

As used herein, the term “C_(i-j) alkylamino,” employed alone or incombination with other terms, refers to a group of formula —NH(alkyl),wherein the alkyl group has i to j carbon atoms. In some embodiments,the alkyl group has 1 to 6 or 1 to 4 carbon atoms. In some embodiments,the alkylamino group is —NH(C₁₋₄ alkyl) such as, for example,methylamino, ethylamino, or propylamino.

As used herein, the term “di-C_(i-j)-alkylamino,” employed alone or incombination with other terms, refers to a group of formula —N(alkyl)₂,wherein each of the two alkyl groups has, independently, i to j carbonatoms. In some embodiments, each alkyl group independently has 1 to 6 or1 to 4 carbon atoms. In some embodiments, the dialkylamino group is—N(C₁₋₄ alkyl)₂ such as, for example, dimethylamino or diethylamino.

As used herein, the term “C_(i-j) alkylthio,” employed alone or incombination with other terms, refers to a group of formula —S-alkyl,wherein the alkyl group has i to j carbon atoms. In some embodiments,the alkyl group has 1 to 6 or 1 to 4 carbon atoms. In some embodiments,the alkylthio group is C₁₋₄ alkylthio such as, for example, methylthioor ethylthio.

As used herein, the term “amino,” employed alone or in combination withother terms, refers to a group of formula —NH₂.

As used herein, the term “aryl,” employed alone or in combination withother terms, refers to a monocyclic or polycyclic (e.g., having 2, 3 or4 fused rings) aromatic hydrocarbon, such as, but not limited to,phenyl, 1-naphthyl, 2-naphthyl, anthracenyl, phenanthrenyl, and thelike. In some embodiments, aryl is C₆₋₁₀ aryl. In some embodiments, thearyl group is a naphthalene ring or phenyl ring. In some embodiments,the aryl group is phenyl.

As used herein, the term “aryl-C_(i-j) alkyl,” employed alone or incombination with other terms, refers to an alkyl group substituted by anaryl group. An example of a aryl-C_(i-j) alkyl group is benzyl.

As used herein, the term “carbonyl”, employed alone or in combinationwith other terms, refers to a —C(O)— group.

As used herein, the term “C_(i-j) cycloalkyl,” employed alone or incombination with other terms, refers to a non-aromatic cyclichydrocarbon moiety having i to j ring-forming carbon atoms, which mayoptionally contain one or more alkenylene groups as part of the ringstructure. Cycloalkyl groups can include mono- or polycyclic (e.g.,having 2, 3 or 4 fused rings) ring systems. Also included in thedefinition of cycloalkyl are moieties that have one or more aromaticrings fused (i.e., having a bond in common with) to the cycloalkyl ring,for example, benzo derivatives of cyclopentane, cyclopentene,cyclohexane, and the like. One or more ring-forming carbon atoms of acycloalkyl group can be oxidized to form carbonyl linkages. In someembodiments, cycloalkyl is C₃₋₁₀ cycloalkyl, C₃₋₇ cycloalkyl, or C₅₋₆cycloalkyl. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl,cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, andthe like. Further exemplary cycloalkyl groups include cyclopropyl,cyclobutyl, cyclopentyl, and cyclohexyl.

As used herein, the term “C_(i-j) cycloalkyl-C_(i-j) alkyl,” employedalone or in combination with other terms, refers to an alkyl groupsubstituted by a cycloalkyl group. An example of a C_(i-j)cycloalkyl-C_(i-j) alkyl group is cyclopropylmethyl.

As used herein, “C_(i-j) haloalkoxy,” employed alone or in combinationwith other terms, refers to a group of formula —O-haloalkyl having i toj carbon atoms. An example haloalkoxy group is OCF₃. An additionalexample haloalkoxy group is OCHF₂. In some embodiments, the haloalkoxygroup is fluorinated only. In some embodiments, the alkyl group has 1 to6 or 1 to 4 carbon atoms. In some embodiments, the haloalkoxy group isC₁₋₄ haloalkoxy.

As used herein, the term “halo,” employed alone or in combination withother terms, refers to a halogen atom selected from F, Cl, I or Br. Insome embodiments, “halo” refers to a halogen atom selected from F, Cl,or Br. In some embodiments, the halo substituent is F.

As used herein, the term “C_(i-j) haloalkyl,” employed alone or incombination with other terms, refers to an alkyl group having from onehalogen atom to 2s+1 halogen atoms which may be the same or different,where “s” is the number of carbon atoms in the alkyl group, wherein thealkyl group has i to j carbon atoms. In some embodiments, the haloalkylgroup is fluorinated only. In some embodiments, the haloalkyl group isfluoromethyl, difluoromethyl, or trifluoromethyl. In some embodiments,the haloalkyl group is trifluoromethyl. In some embodiments, the alkylgroup has 1 to 6 or 1 to 4 carbon atoms.

As used herein, the term “heteroaryl,” employed alone or in combinationwith other terms, refers to a monocyclic or polycyclic (e.g., having 2,3 or 4 fused rings) aromatic heterocylic moiety, having one or moreheteroatom ring members selected from nitrogen, sulfur and oxygen. Insome embodiments, the heteroaryl group has 1, 2, 3, or 4 heteroatom ringmembers. In some embodiments, the heteroaryl group has 1, 2, or 3heteroatom ring members. In some embodiments, the heteroaryl group has 1or 2 heteroatom ring members. In some embodiments, the heteroaryl grouphas 1 heteroatom ring member. In some embodiments, the heteroaryl groupis 5- to 10-membered or 5- to 6-membered. In some embodiments, theheteroaryl group is 5-membered. In some embodiments, the heteroarylgroup is 6-membered. When the heteroaryl group contains more than oneheteroatom ring member, the heteroatoms may be the same or different.The nitrogen atoms in the ring(s) of the heteroaryl group can beoxidized to form N-oxides. Example heteroaryl groups include, but arenot limited to, pyridine, pyrimidine, pyrazine, pyridazine, pyrrole,pyrazole, azolyl, oxazole, isoxazole, thiazole, isothiazole, imidazole,furan, thiophene, triazole, tetrazole, thiadiazole, quinoline,isoquinoline, indole, benzothiophene, benzofuran, benzisoxazole,imidazo[1, 2-b]thiazole, purine, triazine, and the like.

A 5-membered heteroaryl is a heteroaryl group having five ring-formingatoms comprising wherein one or more of the ring-forming atoms areindependently selected from N, O, and S. In some embodiments, the5-membered heteroaryl group has 1, 2, or 3 heteroatom ring members. Insome embodiments, the 5-membered heteroaryl group has 1 or 2 heteroatomring members. In some embodiments, the 5-membered heteroaryl group has 1heteroatom ring member. Example ring-forming members include CH, N, NH,O, and S. Example five-membered ring heteroaryls are thienyl, furyl,pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl,isoxazolyl, 1, 2, 3-triazolyl, tetrazolyl, 1, 2, 3-thiadiazolyl, 1, 2,3-oxadiazolyl, 1, 2, 4-triazolyl, 1, 2, 4-thiadiazolyl, 1, 2,4-oxadiazolyl, 1, 3, 4-triazolyl, 1, 3, 4-thiadiazolyl, and 1, 3,4-oxadiazolyl.

A 6-membered heteroaryl is a heteroaryl group having six ring-formingatoms wherein one or more of the ring-forming atoms is N. In someembodiments, the 6-membered heteroaryl group has 1, 2, or 3 heteroatomring members. In some embodiments, the 6-membered heteroaryl group has 1or 2 heteroatom ring members. In some embodiments, the 6-memberedheteroaryl group has 1 heteroatom ring member. Example ring-formingmembers include CH and N. Example six-membered ring heteroaryls arepyridyl, pyrazinyl, pyrimidinyl, triazinyl, and pyridazinyl.

As used herein, the term “heteroaryl-C_(i-j) alkyl,” employed alone orin combination with other terms, refers to an alkyl group substituted bya heteroaryl group. An example of a heteroaryl-C_(i-j) alkyl group ispyridylmethyl.

As used herein, the term “heterocycloalkyl,” employed alone or incombination with other terms, refers to non-aromatic heterocyclic ringsystem, which may optionally contain one or more unsaturations as partof the ring structure, and which has at least one heteroatom ring memberindependently selected from nitrogen, sulfur and oxygen. In someembodiments, the heterocycloalkyl group has 1, 2, 3, or 4 heteroatomring members. In some embodiments, the heterocycloalkyl group has 1, 2,or 3 heteroatom ring members. In some embodiments, the heterocycloalkylgroup has 1 or 2 heteroatom ring members. In some embodiments, theheterocycloalkyl group has 1 heteroatom ring member. When theheterocycloalkyl group contains more than one heteroatom in the ring,the heteroatoms may be the same or different. Example ring-formingmembers include CH, CH₂, C(O), N, NH, O, S, S(O), and S(O)₂.Heterocycloalkyl groups can include mono- or polycyclic (e.g., having 2,3 or 4 fused rings) ring systems, including spiro systems. Also includedin the definition of heterocycloalkyl are moieties that have one or morearomatic rings fused (i.e., having a bond in common with) to thenon-aromatic ring, for example, 1, 2, 3, 4-tetrahydro-quinoline,dihydrobenzofuran and the like. The carbon atoms or heteroatoms in thering(s) of the heterocycloalkyl group can be oxidized to form acarbonyl, sulfinyl, or sulfonyl group (or other oxidized linkage) or anitrogen atom can be quaternized. In some embodiments, theheterocycloalkyl is 5- to 10-membered, 4- to 10-membered, 4- to7-membered, 5-membered, or 6-membered. Examples of heterocycloalkylgroups include 1, 2, 3, 4-tetrahydro-quinoline, dihydrobenzofuran,azetidine, azepane, pyrrolidine, piperidine, piperazine, morpholine,thiomorpholine, and pyran.

As used herein, the term “heterocycloalkyl-C_(i-j) alkyl,” employedalone or in combination with other terms, refers to an alkyl groupsubstituted by a heterocycloalkyl group. An example of aheterocycloalkyl-C_(i-j) alkyl group is pyrrolidinylmethyl.

The compounds described herein can be asymmetric (e.g., having one ormore stereocenters). All stereoisomers, such as enantiomers anddiastereoisomers, are intended unless otherwise indicated. Compounds ofthe present invention that contain asymmetrically substituted carbonatoms can be isolated in optically active or racemic forms. Methods onhow to prepare optically active forms from optically inactive startingmaterials are known in the art, such as by resolution of racemicmixtures or by stereoselective synthesis. Many geometric isomers ofolefins, C═N double bonds, and the like can also be present in thecompounds described herein, and all such stable isomers are contemplatedin the present invention. Cis and trans geometric isomers of thecompounds of the present invention are described and may be isolated asa mixture of isomers or as separated isomeric forms.

When the compounds of the invention contain a chiral center, thecompounds can be any of the possible stereoisomers. In compounds with asingle chiral center, the stereochemistry of the chiral center can be(R) or (S). In compounds with two chiral centers, the stereochemistry ofthe chiral centers can each be independently (R) or (S) so theconfiguration of the chiral centers can be (R) and (R), (R) and (S); (S)and (R), or (S) and (S). In compounds with three chiral centers, thestereochemistry each of the three chiral centers can each beindependently (R) or (S) so the configuration of the chiral centers canbe (R), (R) and (R); (R), (R) and (S); (R), (S) and (R); (R), (S) and(S); (S), (R) and (R); (S), (R) and (S); (S), (S) and (R); or (S), (S)and (S).

Resolution of racemic mixtures of compounds can be carried out by any ofnumerous methods known in the art. An example method includes fractionalrecrystallization using a chiral resolving acid which is an opticallyactive, salt-forming organic acid. Suitable resolving agents forfractional recrystallization methods are, for example, optically activeacids, such as the D and L forms of tartaric acid, diacetyltartaricacid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid orthe various optically active camphorsulfonic acids such asβ-camphorsulfonic acid. Other resolving agents suitable for fractionalcrystallization methods include stereoisomerically pure forms ofα-methylbenzylamine (e.g., S and R forms, or diastereoisomerically pureforms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine,cyclohexylethylamine, 1, 2-diaminocyclohexane, and the like.

Resolution of racemic mixtures can also be carried out by elution on acolumn packed with an optically active resolving agent (e.g.,dinitrobenzoylphenylglycine). Suitable elution solvent composition canbe determined by one skilled in the art.

Compounds of the invention also include tautomeric forms. Tautomericforms result from the swapping of a single bond with an adjacent doublebond together with the concomitant migration of a proton. Tautomericforms include prototropic tautomers which are isomeric protonationstates having the same empirical formula and total charge. Exampleprototropic tautomers include ketone—enol pairs, amide—imidic acidpairs, lactam—lactim pairs, amide—imidic acid pairs, enamine—iminepairs, and annular forms where a proton can occupy two or more positionsof a heterocyclic system, for example, 1H- and 3H-imidazole, 1H-, 2H-and 4H-1, 2, 4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole.Tautomeric forms can be in equilibrium or sterically locked into oneform by appropriate substitution.

Compounds of the invention can also include all isotopes of atomsoccurring in the intermediates or final compounds. Isotopes includethose atoms having the same atomic number but different mass numbers.

The term “compound” as used herein is meant to include allstereoisomers, geometric isomers, tautomers, and isotopes of thestructures depicted. Compounds herein identified by name or structure asone particular tautomeric form are intended to include other tautomericforms unless otherwise specified (e.g., in the case of purine rings,unless otherwise indicated, when the compound name or structure has the9H tautomer, it is understood that the 7H tautomer is also encompassed).

All compounds, and pharmaceutically acceptable salts thereof, can befound together with other substances such as water and solvents (e.g.,hydrates and solvates) or can be isolated.

In some embodiments, the compounds of the invention, or salts thereof,are substantially isolated. By “substantially isolated” is meant thatthe compound is at least partially or substantially separated from theenvironment in which it was formed or detected. Partial separation caninclude, for example, a composition enriched in a compound of theinvention. Substantial separation can include compositions containing atleast about 50%, at least about 60%, at least about 70%, at least about80%, at least about 90%, at least about 95%, at least about 97%, or atleast about 99% by weight of the compounds of the invention, or saltthereof. Methods for isolating compounds and their salts are routine inthe art.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The expressions “ambient temperature” and “room temperature,” as usedherein, are understood in the art, and refer generally to a temperature,e.g., a reaction temperature, that is about the temperature of the roomin which the reaction is carried out, for example, a temperature fromabout 20° C. to about 30° C.

The present invention also includes pharmaceutically acceptable salts ofthe compounds described herein. As used herein, “pharmaceuticallyacceptable salts” refers to derivatives of the disclosed compoundswherein the parent compound is modified by converting an existing acidor base moiety to its salt form. Examples of pharmaceutically acceptablesalts include, but are not limited to, mineral or organic acid salts ofbasic residues such as amines; alkali or organic salts of acidicresidues such as carboxylic acids; and the like. The pharmaceuticallyacceptable salts of the present invention include the conventionalnon-toxic salts of the parent compound formed, for example, fromnon-toxic inorganic or organic acids. The pharmaceutically acceptablesalts of the present invention can be synthesized from the parentcompound which contains a basic or acidic moiety by conventionalchemical methods. Generally, such salts can be prepared by reacting thefree acid or base forms of these compounds with a stoichiometric amountof the appropriate base or acid in water or in an organic solvent, or ina mixture of the two; generally, non-aqueous media like ether, ethylacetate, alcohols (e.g., methanol, ethanol, iso-propanol, or butanol) oracetonitrile (MeCN) are preferred. Lists of suitable salts are found inRemington's Pharmaceutical Sciences, 17^(th) Ed., (Mack PublishingCompany, Easton, 1985), p. 1418, Berge et al., J. Pharm. Sci., 1977,66(1), 1-19, and in Stahl et al., Handbook of Pharmaceutical Salts:Properties, Selection, and Use, (Wiley, 2002).

The following abbreviations may be used herein: AcOH (acetic acid); Ac₂O(acetic anhydride); aq. (aqueous); atm. (atmosphere(s)); Boc(t-butoxycarbonyl); BOP((benzotriazol-1-yloxy)tris(dimethylamino)phosphoniumhexafluorophosphate); br (broad); Cbz (carboxybenzyl); calc.(calculated); d (doublet); dd (doublet of doublets); DBU(1,8-diazabicyclo[5.4.0]undec-7-ene); DCM (dichloromethane); DIAD (N,N′-diisopropyl azidodicarboxylate); DIEA (N,N-diisopropylethylamine);DIPEA (N, N-diisopropylethylamine); DMF (N, N-dimethylformamide); Et(ethyl); EtOAc (ethyl acetate); g (gram(s)); h (hour(s)); HATU (N, N,N′, N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate); HCl (hydrochloric acid); HPLC (high performanceliquid chromatography); Hz (hertz); IPA (isopropyl alcohol); J (couplingconstant); LCMS (liquid chromatography—mass spectrometry); m(multiplet); M (molar); mCPBA (3-chloroperoxybenzoic acid); MS (Massspectrometry); Me (methyl); MeCN (acetonitrile); MeOH (methanol); mg(milligram(s)); min. (minutes(s)); mL (milliliter(s)); mmol(millimole(s)); N (normal); nM (nanomolar); NMP (N-methylpyrrolidinone);NMR (nuclear magnetic resonance spectroscopy); OTf(trifluoromethanesulfonate); Ph (phenyl); pM (picomolar); RP-HPLC(reverse phase high performance liquid chromatography); s (singlet); t(triplet or tertiary); TBS (tert-butyldimethylsilyl); tert (tertiary);tt (triplet of triplets); TFA (trifluoroacetic acid); THF(tetrahydrofuran); μg (microgram(s)); μL (microliter(s)); μM(micromolar); wt % (weight percent).

Synthesis

Compounds of the invention, including salts thereof, can be preparedusing known organic synthesis techniques and can be synthesizedaccording to any of numerous possible synthetic routes.

The reactions for preparing compounds of the invention can be carriedout in suitable solvents which can be readily selected by one of skillin the art of organic synthesis. Suitable solvents can be substantiallynon-reactive with the starting materials (reactants), the intermediates,or products at the temperatures at which the reactions are carried out,e.g., temperatures which can range from the solvent's freezingtemperature to the solvent's boiling temperature. A given reaction canbe carried out in one solvent or a mixture of more than one solvent.Depending on the particular reaction step, suitable solvents for aparticular reaction step can be selected by the skilled artisan.

Preparation of compounds of the invention can involve the protection anddeprotection of various chemical groups. The need for protection anddeprotection, and the selection of appropriate protecting groups, can bereadily determined by one skilled in the art. The chemistry ofprotecting groups can be found, for example, in P. G. M. Wuts and T. W.Greene, Protective Groups in Organic Synthesis, 4^(th) Ed., Wiley &Sons, Inc., New York (2006), which is incorporated herein by referencein its entirety.

Reactions can be monitored according to any suitable method known in theart. For example, product formation can be monitored by spectroscopicmeans, such as nuclear magnetic resonance spectroscopy (e.g., ¹H or¹³C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), massspectrometry, or by chromatographic methods such as high performanceliquid chromatography (HPLC), liquid chromatography-mass spectroscopy(LCMS), or thin layer chromatography (TLC). Compounds can be purified bythose skilled in the art by a variety of methods, including highperformance liquid chromatography (HPLC) (“Preparative LC-MSPurification: Improved Compound Specific Method Optimization” Karl F.Blom, Brian Glass, Richard Sparks, Andrew P. Combs J. Combi. Chem. 2004,6(6), 874-883, which is incorporated herein by reference in itsentirety) and normal phase silica chromatography.

Compounds of formula 12 can be prepared according to Scheme 1. Aselective cross coupling of iodide in compound 1 with compound offormula 2 under standard cross coupling conditions, such as standardSuzuki coupling conditions [e.g., M is boronic acid or ester, in thepresence of a palladium catalyst and a suitable base such as potassiumcarbonate], or Negishi coupling conditions [e.g., M is Zn-halo, in thepresence of a palladium catalyst] can give compounds of formula 3.Protection of the phenol group in compound 3 with a suitable protectinggroup (PG) such as methyl or benzyl by reacting with methyl iodide orbenzyl chloride in the presence a suitable base such as potassiumcarbonate can generate compounds of formula 4. Introduction of thehydrazine moiety can be achieved via SNAr displacement of the chloridein compound 4 with hydrazine to give compound 5. A condensation reactioncan be performed between compound 5 with compound of formula 6 atelevated temperature to produce compound 7. Installation of ring A canbe achieved via coupling of boronic ester or boronic acid of formula 8with compound 7 under standard Suzuki coupling conditions to givecompound 9, which can be deprotected (e.g. BBr₃ to remove methylprotecting group, or hydrogenation to remove benzyl group) to give thephenol derivative 10. The phenol 10 can be converted to triflate 11using standard conditions (e.g., with triflic anhydride in the presenceof a suitable base such as pyridine). The triflate group of compound 11can be coupled to R¹-M to afford the final product of formula 12 understandard cross coupling conditions, such as Suzuki coupling conditions(when M is boronic acid or boronic ester), or standard Negishi reactionconditions (when M is Zn-halo), or standard Buchwald aminationconditions (e.g. in the presence of a palladium catalyst and a suitablebase such as Cs₂CO₃, when M is H and attached to nitrogen atom of R¹),or standard Ullmann coupling conditions (R¹-M is an alcohol with M=H, inthe presence of a palladium or copper catalyst). Alternatively, when R¹in compound 12 is an alkoxyl group with oxygen attached to the centerring, compound 12 can be prepared by an alkylation reaction of compound10 with a suitable alkylating reagent in the presence a suitable basesuch as potassium carbonate or a Mitsunobu reaction of compound 10 withan appropriate alcohol in the presence of diethyl azodicarboxylate(DEAD) and triphenylphosphine (PPh₃).

Synthetic route as shown in Scheme 2 can be followed to preparecompounds of formula 22. Toward this end, the amino group in compound 13can be first converted to a hydroxyl group (e.g., in the presence ofNaNO₂ in H₂SO₄) to give compound 14. Installation of ring B can beachieved by coupling of a compound 14 with a compound of formula 2 usingsimilar conditions as described in Scheme 1 (e.g., Suzuki coupling,Negishi reaction or Buchwald amination conditions) to give compound 15.Suzuki coupling of compound 15 with boronic ester or acid of formula 8can generate compound 16. Protection of the phenol group in compound 16with a suitable protecting group (PG) such as methyl or benzyl (e.g., byreacting with methyl iodide or benzyl chloride in the presence of asuitable base such as potassium carbonate) can give compound 17.Installation of a chlorine substituent onto the pyrazine ring can beachieved by a two-step sequence [e.g., oxidation withmeta-chloroperoxybenzoic acid (m-CPBA), followed by treatment withPOCl₃] to give compound 18, followed by a SNAr displacement of thechlorine with hydrazine to generate compound 19. Condensation ofcompound 19 with compound of formula 6 can give the bicyclic compound20. Removal of the protecting group PG can reveal the phenol group whichcan react with triflic anhydride to generate the triflate 21. Thetriflate group of compound 21 can be coupled to R¹-M under standardcross coupling reactions as described in Scheme 1 (e.g., Suzukicoupling, Negishi coupling, Buchwald amination or Ullmann couplingconditions) to give compound of formula 22. Alternatively, if R¹ is analkoxyl group with oxygen attached to the pyrazine ring, the protectionstep of compound 16 can be replaced by an ether formation reaction(e.g., alkylation in the presence of a base such as potassium carbonate,or Mitsunobu reaction with DEAD and Ph₃P) to introduce the R¹ thenfollowing similar reaction sequences as described above can give thefinal ether compound 22.

Compounds of formula 28 can be prepared using procedures as outlined inScheme 3 starting from compounds of formula 23 which can be prepared asdescribed in Scheme 1 or Scheme 2. Treatment of the hydrazine derivative23 with carbonyl diimidazole or equivalent can generate compound 24,which can undergo Suzuki coupling with boronic ester/acid 8 to installring A to give compound 25. Alkylation of compound 25 with anappropriate alkylating reagent R²-Lg (Lg is a leaving group such as Clor Br) in the presence of a suitable base such as potassium carbonatecan give compound 26. Alternatively, if R² is an aromatic group, thecoupling of R²-Lg to compound 25 can be performed under Buchwaldamination conditions (e.g., in the presence of a palladium catalyst anda suitable base). Removal of the protecting group PG in compound 26,followed by reacting with triflic anhydride (Tf₂O) can give the triflate27. The triflate group of compound 27 can be coupled to R¹-M usingsimilar procedures (e.g., Suzuki coupling, Negishi coupling, Buchwaldamination, or Ullmann coupling conditions) as described in Scheme 1 togive the final compound of formula 28. For compound 28 with R¹ as anether group, the ether moiety can also be introduced using similarprocedures as described in Scheme 1 or Scheme 2.

Methods of Use

Compounds of the invention are LSD1 inhibitors and, thus, are useful intreating diseases and disorders associated with activity of LSD1. Forthe uses described herein, any of the compounds of the invention,including any of the embodiments thereof, may be used.

In some embodiments, the compounds of the invention are selective forLSD1 over LSD2, meaning that the compounds bind to or inhibit LSD1 withgreater affinity or potency, compared to LSD2. In general, selectivitycan be at least about 5-fold, at least about 10-fold, at least about20-fold, at least about 50-fold, at least about 100-fold, at least about200-fold, at least about 500-fold or at least about 1000-fold.

As inhibitors of LSD1, the compounds of the invention are useful intreating LSD1-mediated diseases and disorders. The term “LSD1-mediateddisease” or “LSD1-mediated disorder” refers to any disease or conditionin which LSD1 plays a role, or where the disease or condition isassociated with expression or activity of LSD1. The compounds of theinvention can therefore be used to treat or lessen the severity ofdiseases and conditions where LSD1 is known to play a role.

Diseases and conditions treatable using the compounds of the inventioninclude generally cancers, inflammation, autoimmune diseases, viralinduced pathogenesis, beta-globinopathies, and other diseases linked toLSD1 activity.

Cancers treatable using compounds according to the present inventioninclude, for example, hematological cancers, sarcomas, lung cancers,gastrointestinal cancers, genitourinary tract cancers, liver cancers,bone cancers, nervous system cancers, gynecological cancers, and skincancers.

Example hematological cancers include, for example, lymphomas andleukemias such as acute lymphoblastic leukemia (ALL), acute myelogenousleukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocyticleukemia (CLL), chronic myelogenous leukemia (CML), diffuse large B-celllymphoma (DLBCL), mantle cell lymphoma, Non-Hodgkin lymphoma (includingrelapsed or refractory NHL and recurrent follicular), Hodgkin lymphoma,myeloproliferative diseases (e.g., primary myelofibrosis (PMF),polycythemia vera (PV), essential thrombocytosis (ET)), myelodysplasiasyndrome (MDS), and multiple myeloma.

Example sarcomas include, for example, chondrosarcoma, Ewing's sarcoma,osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma,myxoma, rhabdomyoma, fibroma, lipoma, harmatoma, and teratoma.

Example lung cancers include, for example, non-small cell lung cancer(NSCLC), bronchogenic carcinoma (squamous cell, undifferentiated smallcell, undifferentiated large cell, adenocarcinoma), alveolar(bronchiolar) carcinoma, bronchial adenoma, chondromatous hamartoma, andmesothelioma.

Example gastrointestinal cancers include, for example, cancers of theesophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma,lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas(ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoidtumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoidtumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma,fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma,hamartoma, leiomyoma), and colorectal cancer.

Example genitourinary tract cancers include, for example, cancers of thekidney (adenocarcinoma, Wilm's tumor [nephroblastoma]), bladder andurethra (squamous cell carcinoma, transitional cell carcinoma,adenocarcinoma), prostate (adenocarcinoma, sarcoma), and testis(seminoma, teratoma, embryonal carcinoma, teratocarcinoma,choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma,fibroadenoma, adenomatoid tumors, lipoma).

Example liver cancers include, for example, hepatoma (hepatocellularcarcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma,hepatocellular adenoma, and hemangioma.

Example bone cancers include, for example, osteogenic sarcoma(osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma,chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cellsarcoma), multiple myeloma, malignant giant cell tumor chordoma,osteochronfroma (osteocartilaginous exostoses), benign chondroma,chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant celltumors

Example nervous system cancers include, for example, cancers of theskull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans),meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma,meduoblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastomamultiform, oligodendroglioma, schwannoma, retinoblastoma, congenitaltumors), and spinal cord (neurofibroma, meningioma, glioma, sarcoma), aswell as neuroblastoma and Lhermitte-Duclos disease.

Example gynecological cancers include, for example, cancers of theuterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumorcervical dysplasia), ovaries (ovarian carcinoma (serouscystadenocarcinoma, mucinous cystadenocarcinoma, unclassifiedcarcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors,dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma,intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma),vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma(embryonal rhabdomyosarcoma), and fallopian tubes (carcinoma).

Example skin cancers include, for example, melanoma, basal cellcarcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplasticnevi, lipoma, angioma, dermatofibroma, and keloids.

The compounds of the invention can further be used to treat cancer typeswhere LSD1 may be overexpressed including, for example, breast,prostate, head and neck, laryngeal, oral, and thyroid cancers (e.g.,papillary thyroid carcinoma).

The compounds of the invention can further be used to treat geneticdisorders such as Cowden syndrome and Bannayan-Zonana syndrome.

The compounds of the invention can further be used to treat viraldiseases such as herpes simplex virus (HSV), varicella zoster virus(VZV), human cytomegalovirus, hepatitis B virus (HBV), and adenovirus.

The compounds of the invention can further be used to treatbeta-globinopathies including, for example, beta-thalassemia and sicklecell anemia.

As used herein, the term “contacting” refers to the bringing together ofindicated moieties in an in vitro system or an in vivo system. Forexample, “contacting” a LSD1 protein with a compound of the inventionincludes the administration of a compound of the present invention to anindividual or patient, such as a human, having a LSD1 protein, as wellas, for example, introducing a compound of the invention into a samplecontaining a cellular or purified preparation containing the LSD1protein.

As used herein, the term “individual” or “patient, ” usedinterchangeably, refers to any animal, including mammals, preferablymice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep,horses, or primates, and most preferably humans.

As used herein, the phrase “therapeutically effective amount” refers tothe amount of active compound or pharmaceutical agent that elicits thebiological or medicinal response that is being sought in a tissue,system, animal, individual or human by a researcher, veterinarian,medical doctor or other clinician.

As used herein, the term “treating” or “treatment” refers to inhibitingthe disease; for example, inhibiting a disease, condition or disorder inan individual who is experiencing or displaying the pathology orsymptomatology of the disease, condition or disorder (i.e., arrestingfurther development of the pathology and/or symptomatology) orameliorating the disease; for example, ameliorating a disease, conditionor disorder in an individual who is experiencing or displaying thepathology or symptomatology of the disease, condition or disorder (i.e.,reversing the pathology and/or symptomatology) such as decreasing theseverity of disease.

As used herein, the term “preventing” or “prevention” refers topreventing the disease; for example, preventing a disease, condition ordisorder in an individual who may be predisposed to the disease,condition or disorder but does not yet experience or display thepathology or symptomatology of the disease.

Combination Therapies

The compounds of the invention can be used in combination treatmentswhere the compound of the invention is administered in conjunction withother treatments such as the administration of one or more additionaltherapeutic agents. The additional therapeutic agents are typicallythose which are normally used to treat the particular condition to betreated. The additional therapeutic agents can include, e.g.,chemotherapeutics, anti-inflammatory agents, steroids,immunosuppressants, as well as Bcr-Abl, Flt-3, RAF, FAK, JAK, PIM, PI3Kinhibitors for treatment of LSD1-mediated diseases, disorders orconditions. The one or more additional pharmaceutical agents can beadministered to a patient simultaneously or sequentially.

In some embodiments, the compounds of the invention can be used incombination with a therapeutic agent that targets an epigeneticregulator. Examples of epigenetic regulators include the histone lysinemethyltransferases, histone arginine methyl transferases, histonedemethylases, histone deacetylases, histone acetylases, and DNAmethyltransferases. Histone deacetylase inhibitors include, e.g.,vorinostat.

For treating cancer and other proliferative diseases, the compounds ofthe invention can be used in combination with chemotherapeutic agents,agonists or antagonists of nuclear receptors, or otheranti-proliferative agents. The compounds of the invention can also beused in combination with medical therapy such as surgery orradiotherapy, e.g., gamma-radiation, neutron beam radiotherapy, electronbeam radiotherapy, proton therapy, brachytherapy, and systemicradioactive isotopes. Examples of suitable chemotherapeutic agentsinclude any of: abarelix, aldesleukin, alemtuzumab, alitretinoin,allopurinol, altretamine, anastrozole, arsenic trioxide, asparaginase,azacitidine, bevacizumab, bexarotene, bleomycin, bortezombi, bortezomib,busulfan intravenous, busulfan oral, calusterone, capecitabine,carboplatin, carmustine, cetuximab, chlorambucil, cisplatin, cladribine,clofarabine, cyclophosphamide, cytarabine, dacarbazine, dactinomycin,dalteparin sodium, dasatinib, daunorubicin, decitabine, denileukin,denileukin diftitox, dexrazoxane, docetaxel, doxorubicin, dromostanolonepropionate, eculizumab, epirubicin, erlotinib, estramustine, etoposidephosphate, etoposide, exemestane, fentanyl citrate, filgrastim,floxuridine, fludarabine, fluorouracil, fulvestrant, gefitinib,gemcitabine, gemtuzumab ozogamicin, goserelin acetate, histrelinacetate, ibritumomab tiuxetan, idarubicin, ifosfamide, imatinibmesylate, interferon alfa 2a, irinotecan, lapatinib ditosylate,lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisole,lomustine, meclorethamine, megestrol acetate, melphalan, mercaptopurine,methotrexate, methoxsalen, mitomycin C, mitotane, mitoxantrone,nandrolone phenpropionate, nelarabine, nofetumomab, oxaliplatin,paclitaxel, pamidronate, panitumumab, pegaspargase, pegfilgrastim,pemetrexed disodium, pentostatin, pipobroman, plicamycin, procarbazine,quinacrine, rasburicase, rituximab, ruxolitinib, sorafenib,streptozocin, sunitinib, sunitinib maleate, tamoxifen, temozolomide,teniposide, testolactone, thalidomide, thioguanine, thiotepa, topotecan,toremifene, tositumomab, trastuzumab, tretinoin, uracil mustard,valrubicin, vinblastine, vincristine, vinorelbine, vorinostat, andzoledronate.

For treating cancer and other proliferative diseases, the compounds ofthe invention can be used in combination with ruxolitinib.

For treating autoimmune or inflammatory conditions, the compound of theinvention can be administered in combination with a corticosteroid suchas triamcinolone, dexamethasone, fluocinolone, cortisone, prednisolone,or flumetholone.

For treating autoimmune or inflammatory conditions, the compound of theinvention can be administered in combination with an immune suppressantsuch as fluocinolone acetonide (Retisert®), rimexolone (AL-2178, Vexol,Alcon), or cyclosporine (Restasis®).

For treating autoimmune or inflammatory conditions, the compound of theinvention can be administered in combination with one or more additionalagents selected from Dehydrex™ (Holles Labs), Civamide (Opko), sodiumhyaluronate (Vismed, Lantibio/TRB Chemedia), cyclosporine (ST-603,Sirion Therapeutics), ARG101(T) (testosterone, Argentis), AGR1012(P)(Argentis), ecabet sodium (Senju-Ista), gefarnate (Santen),15-(s)-hydroxyeicosatetraenoic acid (15(S)-HETE), cevilemine,doxycycline (ALTY-0501, Alacrity), minocycline, iDestrin™ (NP50301,Nascent Pharmaceuticals), cyclosporine A (Nova22007, Novagali),oxytetracycline (Duramycin, MOLI1901, Lantibio), CF101 (2S, 3S, 4R,5R)-3,4-dihydroxy-5-[6-[(3-iodophenyl)methylamino]purin-9-yl]-N-methyl-oxolane-2-carbamyl,Can-Fite Biopharma), voclosporin (LX212 or LX214, Lux Biosciences),ARG103 (Agentis), RX-10045 (synthetic resolvin analog, Resolvyx), DYN15(Dyanmis Therapeutics), rivoglitazone (DE011, Daiichi Sanko), TB4(RegeneRx), OPH-01 (Ophtalmis Monaco), PCS101 (Pericor Science), REV1-31(Evolutec), Lacritin (Senju), rebamipide (Otsuka-Novartis), OT-551(Othera), PAI-2 (University of Pennsylvania and Temple University),pilocarpine, tacrolimus, pimecrolimus (AMS981, Novartis), loteprednoletabonate, rituximab, diquafosol tetrasodium (INS365, Inspire), KLS-0611(Kissei Pharmaceuticals), dehydroepiandrosterone, anakinra, efalizumab,mycophenolate sodium, etanercept (Embrel®), hydroxychloroquine, NGX267(TorreyPines Therapeutics), or thalidomide.

For treating beta-thalassemia or sickle cell disease, the compound ofthe invention can be administered in combination with one or moreadditional agents such as Hydrea® (hydroxyurea).

In some embodiments, the compound of the invention can be administeredin combination with one or more agents selected from an antibiotic,antiviral, antifungal, anesthetic, anti-inflammatory agents includingsteroidal and non-steroidal anti-inflammatories, and anti-allergicagents. Examples of suitable medicaments include aminoglycosides such asamikacin, gentamycin, tobramycin, streptomycin, netilmycin, andkanamycin; fluoroquinolones such as ciprofloxacin, norfloxacin,ofloxacin, trovafloxacin, lomefloxacin, levofloxacin, and enoxacin;naphthyridine; sulfonamides; polymyxin; chloramphenicol; neomycin;paramomycin; colistimethate; bacitracin; vancomycin; tetracyclines;rifampin and its derivatives (“rifampins”); cycloserine; beta-lactams;cephalosporins; amphotericins; fluconazole; flucytosine; natamycin;miconazole; ketoconazole; corticosteroids; diclofenac; flurbiprofen;ketorolac; suprofen; cromolyn; lodoxamide; levocabastin; naphazoline;antazoline; pheniramine; or azalide antibiotic.

Other examples of agents, one or more of which a provided compound mayalso be combined with include: a treatment for Alzheimer's Disease suchas donepezil and rivastigmine; a treatment for Parkinson's Disease suchas L-DOPA/carbidopa, entacapone, ropinirole, pramipexole, bromocriptine,pergolide, trihexyphenidyl, and amantadine; an agent for treatingmultiple sclerosis (MS) such as beta interferon (e.g., Avonex® andRebif®), glatiramer acetate, and mitoxantrone; a treatment for asthmasuch as albuterol and montelukast; an agent for treating schizophreniasuch as zyprexa, risperdal, seroquel, and haloperidol; ananti-inflammatory agent such as a corticosteroid, such as dexamethasoneor prednisone, a TNF blocker, IL-1 RA, azathioprine, cyclophosphamide,and sulfasalazine; an immunomodulatory agent, includingimmunosuppressive agents, such as cyclosporin, tacrolimus, rapamycin,mycophenolate mofetil, an interferon, a corticosteroid,cyclophosphamide, azathioprine, and sulfasalazine; a neurotrophic factorsuch as an acetylcholinesterase inhibitor, an MAO inhibitor, aninterferon, an anti-convulsant, an ion channel blocker, riluzole, or ananti-Parkinson's agent; an agent for treating cardiovascular diseasesuch as a beta-blocker, an ACE inhibitor, a diuretic, a nitrate, acalcium channel blocker, or a statin; an agent for treating liverdisease such as a corticosteroid, cholestyramine, an interferon, and ananti-viral agent; an agent for treating blood disorders such as acorticosteroid, an anti-leukemic agent, or a growth factor; or an agentfor treating immunodeficiency disorders such as gamma globulin.

Formulation, Dosage Forms and Administration

When employed as pharmaceuticals, the compounds of the invention can beadministered in the form of pharmaceutical compositions. Thesecompositions can be prepared in a manner well known in thepharmaceutical art, and can be administered by a variety of routes,depending upon whether local or systemic treatment is desired and uponthe area to be treated. Administration may be topical (includingtransdermal, epidermal, ophthalmic and to mucous membranes includingintranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalationor insufflation of powders or aerosols, including by nebulizer;intratracheal or intranasal), oral or parenteral. Parenteraladministration includes intravenous, intraarterial, subcutaneous,intraperitoneal intramuscular or injection or infusion; or intracranial,e.g., intrathecal or intraventricular, administration. Parenteraladministration can be in the form of a single bolus dose, or may be, forexample, by a continuous perfusion pump. Pharmaceutical compositions andformulations for topical administration may include transdermal patches,ointments, lotions, creams, gels, drops, suppositories, sprays, liquidsand powders. Conventional pharmaceutical carriers, aqueous, powder oroily bases, thickeners and the like may be necessary or desirable.

This invention also includes pharmaceutical compositions which contain,as the active ingredient, the compound of the invention or apharmaceutically acceptable salt thereof, in combination with one ormore pharmaceutically acceptable carriers (excipients). In someembodiments, the composition is suitable for topical administration. Inmaking the compositions of the invention, the active ingredient istypically mixed with an excipient, diluted by an excipient or enclosedwithin such a carrier in the form of, for example, a capsule, sachet,paper, or other container. When the excipient serves as a diluent, itcan be a solid, semi-solid, or liquid material, which acts as a vehicle,carrier or medium for the active ingredient. Thus, the compositions canbe in the form of tablets, pills, powders, lozenges, sachets, cachets,elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solidor in a liquid medium), ointments containing, for example, up to 10% byweight of the active compound, soft and hard gelatin capsules,suppositories, sterile injectable solutions, and sterile packagedpowders.

In preparing a formulation, the active compound can be milled to providethe appropriate particle size prior to combining with the otheringredients. If the active compound is substantially insoluble, it canbe milled to a particle size of less than 200 mesh. If the activecompound is substantially water soluble, the particle size can beadjusted by milling to provide a substantially uniform distribution inthe formulation, e.g., about 40 mesh.

The compounds of the invention may be milled using known millingprocedures such as wet milling to obtain a particle size appropriate fortablet formation and for other formulation types. Finely divided(nanoparticulate) preparations of the compounds of the invention can beprepared by processes known in the art, e.g., see International App. No.WO 2002/000196.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. Theformulations can additionally include: lubricating agents such as talc,magnesium stearate, and mineral oil; wetting agents; emulsifying andsuspending agents; preserving agents such as methyl- andpropylhydroxy-benzoates; sweetening agents; and flavoring agents. Thecompositions of the invention can be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.

The compositions can be formulated in a unit dosage form, each dosagecontaining from about 5 to about 1,000 mg (1 g), more usually about 100mg to about 500 mg, of the active ingredient. The term “unit dosageforms” refers to physically discrete units suitable as unitary dosagesfor human subjects and other mammals, each unit containing apredetermined quantity of active material calculated to produce thedesired therapeutic effect, in association with a suitablepharmaceutical excipient.

The active compound may be effective over a wide dosage range and isgenerally administered in a pharmaceutically effective amount. It willbe understood, however, that the amount of the compound actuallyadministered will usually be determined by a physician, according to therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered, theage, weight, and response of the individual patient, the severity of thepatient's symptoms, and the like.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention. When referring to thesepreformulation compositions as homogeneous, the active ingredient istypically dispersed evenly throughout the composition so that thecomposition can be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules. This solid preformulation isthen subdivided into unit dosage forms of the type described abovecontaining from, for example, about 0.1 to about 1000 mg of the activeingredient of the present invention.

The tablets or pills of the present invention can be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction. For example, the tablet or pill can comprise an inner dosage andan outer dosage component, the latter being in the form of an envelopeover the former. The two components can be separated by an enteric layerwhich serves to resist disintegration in the stomach and permit theinner component to pass intact into the duodenum or to be delayed inrelease. A variety of materials can be used for such enteric layers orcoatings, such materials including a number of polymeric acids andmixtures of polymeric acids with such materials as shellac, cetylalcohol, and cellulose acetate.

The liquid forms in which the compounds and compositions of the presentinvention can be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil, or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. In some embodiments, the compositions are administered by theoral or nasal respiratory route for local or systemic effect.Compositions can be nebulized by use of inert gases. Nebulized solutionsmay be breathed directly from the nebulizing device or the nebulizingdevice can be attached to a face masks tent, or intermittent positivepressure breathing machine. Solution, suspension, or powder compositionscan be administered orally or nasally from devices which deliver theformulation in an appropriate manner.

Topical formulations can contain one or more conventional carriers. Insome embodiments, ointments can contain water and one or morehydrophobic carriers selected from, for example, liquid paraffin,polyoxyethylene alkyl ether, propylene glycol, white vaseline, and thelike. Carrier compositions of creams can be based on water incombination with glycerol and one or more other components, e.g.,glycerinemonostearate, PEG-glycerinemonostearate and cetylstearylalcohol. Gels can be formulated using isopropyl alcohol and water,suitably in combination with other components such as, for example,glycerol, hydroxyethyl cellulose, and the like. In some embodiments,topical formulations contain at least about 0.1, at least about 0.25, atleast about 0.5, at least about 1, at least about 2, or at least about 5wt % of the compound of the invention. The topical formulations can besuitably packaged in tubes of, for example, 100 g which are optionallyassociated with instructions for the treatment of the select indication,e.g., psoriasis or other skin condition.

The amount of compound or composition administered to a patient willvary depending upon what is being administered, the purpose of theadministration, such as prophylaxis or therapy, the state of thepatient, the manner of administration, and the like. In therapeuticapplications, compositions can be administered to a patient alreadysuffering from a disease in an amount sufficient to cure or at leastpartially arrest the symptoms of the disease and its complications.Effective doses will depend on the disease condition being treated aswell as by the judgment of the attending clinician depending uponfactors such as the severity of the disease, the age, weight and generalcondition of the patient, and the like.

The compositions administered to a patient can be in the form ofpharmaceutical compositions described above. These compositions can besterilized by conventional sterilization techniques, or may be sterilefiltered. Aqueous solutions can be packaged for use as is, orlyophilized, the lyophilized preparation being combined with a sterileaqueous carrier prior to administration. The pH of the compoundpreparations typically will be between 3 and 11, more preferably from 5to 9 and most preferably from 7 to 8. It will be understood that use ofcertain of the foregoing excipients, carriers, or stabilizers willresult in the formation of pharmaceutical salts.

The therapeutic dosage of a compound of the present invention can varyaccording to, for example, the particular use for which the treatment ismade, the manner of administration of the compound, the health andcondition of the patient, and the judgment of the prescribing physician.The proportion or concentration of a compound of the invention in apharmaceutical composition can vary depending upon a number of factorsincluding dosage, chemical characteristics (e.g., hydrophobicity), andthe route of administration. For example, the compounds of the inventioncan be provided in an aqueous physiological buffer solution containingabout 0.1 to about 10% w/v of the compound for parenteraladministration. Some typical dose ranges are from about 1 μg/kg to about1 g/kg of body weight per day. In some embodiments, the dose range isfrom about 0.01 mg/kg to about 100 mg/kg of body weight per day. Thedosage is likely to depend on such variables as the type and extent ofprogression of the disease or disorder, the overall health status of theparticular patient, the relative biological efficacy of the compoundselected, formulation of the excipient, and its route of administration.Effective doses can be extrapolated from dose-response curves derivedfrom in vitro or animal model test systems.

The compositions of the invention can further include one or moreadditional pharmaceutical agents such as a chemotherapeutic, steroid,anti-inflammatory compound, or immunosuppressant, examples of which arelisted hereinabove.

Labeled Compounds and Assay Methods

Another aspect of the present invention relates to labeled compounds ofthe invention (radio-labeled, fluorescent-labeled, etc.) that would beuseful not only in imaging techniques but also in assays, both in vitroand in vivo, for localizing and quantitating LSD1 in tissue samples,including human, and for identifying LSD1 ligands by inhibition bindingof a labeled compound. Accordingly, the present invention includes LSD1assays that contain such labeled compounds.

The present invention further includes isotopically-labeled compounds ofthe invention. An “isotopically” or “radio-labeled” compound is acompound of the invention where one or more atoms are replaced orsubstituted by an atom having an atomic mass or mass number differentfrom the atomic mass or mass number typically found in nature (i.e.,naturally occurring). Suitable radionuclides that may be incorporated incompounds of the present invention include but are not limited to ³H(also written as T for tritium), ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O,¹⁸F, ³⁵S, ³⁶Cl, ⁸²Br, ⁷⁵Br, ⁷⁶Br, ⁷⁷Br, ¹²³I, ¹²⁴I, ¹²⁵I and ¹³¹I. Theradionuclide that is incorporated in the instant radio-labeled compoundswill depend on the specific application of that radio-labeled compound.

It is to be understood that a “radio-labeled” or “labeled compound” is acompound that has incorporated at least one radionuclide. In someembodiments the radionuclide is selected from the group consisting of³H, ¹⁴C, ¹²⁵I, ³⁵S and ⁸²Br. In some embodiments, the compoundincorporates 1, 2, or 3 deuterium atoms.

The present invention can further include synthetic methods forincorporating radio-isotopes into compounds of the invention. Syntheticmethods for incorporating radio-isotopes into organic compounds are wellknown in the art, and an ordinary skill in the art will readilyrecognize the methods applicable for the compounds of invention.

A labeled compound of the invention can be used in a screening assay toidentify/evaluate compounds. For example, a newly synthesized oridentified compound (i.e., test compound) which is labeled can beevaluated for its ability to bind LSD1 by monitoring its concentrationvariation when contacting with LSD1, through tracking of the labeling.For example, a test compound (labeled) can be evaluated for its abilityto reduce binding of another compound which is known to bind to LSD1(i.e., standard compound). Accordingly, the ability of a test compoundto compete with the standard compound for binding to LSD1 directlycorrelates to its binding affinity. Conversely, in some other screeningassays, the standard compound is labeled and test compounds areunlabeled. Accordingly, the concentration of the labeled standardcompound is monitored in order to evaluate the competition between thestandard compound and the test compound, and the relative bindingaffinity of the test compound is thus ascertained.

The invention will be described in greater detail by way of specificexamples. The following examples are offered for illustrative purposes,and are not intended to limit the invention in any manner. Those ofskill in the art will readily recognize a variety of non-criticalparameters which can be changed or modified to yield essentially thesame results. The compounds of the Examples were found to be inhibitorsof LSD1 as described below.

EXAMPLES

Experimental procedures for compounds of the invention are providedbelow. Preparatory LC-MS purifications of some of the compounds preparedwere performed on Waters mass directed fractionation systems. The basicequipment setup, protocols, and control software for the operation ofthese systems have been described in detail in the literature. See e.g.“Two-Pump At Column Dilution Configuration for Preparative LC-MS”, K.Blom, J. Combi. Chem., 4, 295 (2002); “Optimizing Preparative LC-MSConfigurations and Methods for Parallel Synthesis Purification”, K.Blom, R. Sparks, J. Doughty, G. Everlof, T. Haque, A. Combs, J. Combi.Chem., 5, 670 (2003); and “Preparative LC-MS Purification: ImprovedCompound Specific Method Optimization”, K. Blom, B. Glass, R. Sparks, A.Combs, J. Combi. Chem., 6, 874-883 (2004). The compounds separated weretypically subjected to analytical liquid chromatography massspectrometry (LCMS) for purity check under the following conditions:Instrument; Agilent 1100 series, LC/MSD, Column: Waters Sunfire™ C₁₈ 5μm particle size, 2.1×5.0 mm, Buffers: mobile phase A: 0.025% TFA inwater and mobile phase B: acetonitrile; gradient 2% to 80% of B in 3minutes with flow rate 2.0 mL/minute.

Some of the compounds prepared were also separated on a preparativescale by reverse-phase high performance liquid chromatography (RP-HPLC)with MS detector or flash chromatography (silica gel) as indicated inthe Examples. Typical preparative reverse-phase high performance liquidchromatography (RP-HPLC) column conditions are as follows:

pH=2 purifications: Waters Sunfire™ C₁₈ 5 μm particle size, 19×100 mmcolumn, eluting with mobile phase A: 0.1% TFA (trifluoroacetic acid) inwater and mobile phase B: acetonitrile; the flow rate was 30 mL/minute,the separating gradient was optimized for each compound using theCompound Specific Method Optimization protocol as described in theliterature [see “Preparative LCMS Purification: Improved CompoundSpecific Method Optimization”, K. Blom, B. Glass, R. Sparks, A. Combs,J. Comb. Chem., 6, 874-883 (2004)]. Typically, the flow rate used withthe 30×100 mm column was 60 mL/minute.

pH=10 purifications: Waters XBridge C₁₈ 5 μm particle size, 19×100 mmcolumn, eluting with mobile phase A: 0.15% NH₄OH in water and mobilephase B: acetonitrile; the flow rate was 30 mL/minute, the separatinggradient was optimized for each compound using the Compound SpecificMethod Optimization protocol as described in the literature [See“Preparative LCMS Purification: Improved Compound Specific MethodOptimization”, K. Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem.,6, 874-883 (2004)]. Typically, the flow rate used with 30×100 mm columnwas 60 mL/minute.

EXAMPLES Example 14-{5-(4-methylphenyl)-8-[(3R)-pyrrolidin-3-ylmethoxy][1,2,4]triazolo[4,3-a]pyridin-6-yl}benzonitrile

Step 1: 2,5-dichloro-6-(4-methylphenyl)pyridin-3-ol

A mixture of 2,5-dichloro-6-iodopyridin-3-ol (Aldrich, cat# ADE000183,750 mg, 2.6 mmol), palladium acetate (58.1 mg, 0.259 mmol),tri-o-tolylphosphine (158 mg, 0.518 mmol), sodium carbonate (549 mg,5.18 mmol), and (4-methylphenyl)boronic acid (616 mg, 4.53 mmol) in1,2-dimethoxyethane (20 mL) and water (5.0 mL) was first purged withnitrogen and then stirred and heated at 80° C. for 2 h until completionof the reaction. The reaction mixture was passed through a pad ofCelite, rinsed with EtOAc and the filtrate was concentrated. The residuewas then purified via column chromatography (0% to 15% methanol in DCM)to give the product as a dark red solid (700 mg, quant.). LC/MScalculated for C₁₂H₁₀C₁₂NO (M+H)⁺: m/z=254.0; found 254.0.

Step 2: tert-butyl(3R)-3-({[2,5-dichloro-6-(4-methylphenyl)pyridin-3-yl]oxy}methyl)pyrrolidine-1-carboxylate

To a solution of 2,5-dichloro-6-(4-methylphenyl)pyridin-3-ol (700 mg, 3mmol), tert-butyl (3R)-3-(hydroxymethyl)pyrrolidine-1-carboxylate (ArkPharm, cat# AK-25400, 1.11 g, 5.51 mmol), and triphenylphosphine (1.44g, 5.51 mmol) in tetrahydrofuran (25 mL) at room temperature was addeddiethyl azodicarboxylate (40 wt. % in toluene, 2.50 mL, 6.35 mmol)dropwise. The reaction mixture was stirred at room temperature for 2 hthen concentrated. The residue was purified via column chromatography(15% to 50% EtOAc in hexanes) to give the product as a white foamy solid(891 mg, 70%). LC/MS calculated for C₁₈H₁₉C₁₂N₂O₃ [M-(t-butyl)+2H]⁺:m/z=381.1; found 381.1.

Step 3: tert-butyl(3R)-3-({[5-chloro-2-hydrazino-6-(4-methylphenyl)pyridin-3-yl]oxy}methyl)pyrrolidine-1-carboxylate

To a mixture of(3R)-3-({[2,5-dichloro-6-(4-methylphenyl)pyridin-3-yl]oxy}methyl)pyrrolidine-1-carboxylate (250 mg, 0.56 mmol) in isopropyl alcohol (1.8mL) was added hydrazine hydrate (1.8 mL, 37 mmol). The resulting mixturewas heated at 130° C. for 3 h under microwave conditions. The resultingmixture was then cooled to room temperature, diluted with methanol, andconcentrated to give the crude product as a white solid, which was useddirectly in the next step. LC-MS calculated for C₂₂H₃₀ClN₄O₃[M+H]⁺:m/z=433.2; found 433.2.

Step 4: tert-butyl(3R)-3-({[6-chloro-5-(4-methylphenyl)[1,2,4]triazolo[4,3-a]pyridin-8-yl]oxy}methyl)pyrrolidine-1-carboxylate

The crude product from Step 3 was first dissolved in ethyl orthoformate(5.0 mL), and then heated at 95° C. for 1 h. The mixture was cooled toroom temperature then concentrated. The residue was purified via columnchromatography (15% to 75% EtOAc in hexanes) to give the product as anorange solid (229 mg, 91% two steps). LC/MS calculated for C₂₃H₂₈ClN₄O₃[M+H]⁺: m/z=443.2; found 443.2.

Step 5: tert-butyl(3R)-3-({[6-(4-cyanophenyl)-5-(4-methylphenyl)[1,2,4]triazolo[4,3-a]pyridin-8-yl]oxy}methyl)pyrrolidine-1-carboxylate

A mixture of tert-butyl(3R)-3-({[6-chloro-5-(4-methylphenyl)[1,2,4]triazolo[4,3-a]pyridin-8-yl]oxy}methyl)pyrrolidine-1-carboxylate(48.6 mg, 0.11 mmol), (4-cyanophenyl) boronic acid (40.3 mg, 0.27 mmol),tetrakis(triphenylphosphine)palladium(0) (25.4 mg, 0.022 mmol) andNa₂CO₃ solution (1.0 M in water, 0.40 mL) in 1,4-dioxane (1.0 mL) wasfirst purged with nitrogen, then stirred and heated at 110° C. for 3 h.The reaction mixture was then cooled to room temperature, passed througha pad of Celite and concentrated. The resulting residue was purified bycolumn chromatography (0% to 75% EtOAc in hexanes) to give the productas a slightly yellow solid, which was used directly in the next step.LC-MS calculated for C₃₀H₃₂N₅O₃ [M+H]⁺: m/z=510.2; found 510.2.

Step 6:4-{5-(4-methylphenyl)-8-[(3R)-pyrrolidin-3-ylmethoxy][1,2,4]triazolo[4,3-a]pyridin-6-yl}benzonitrile

To a solution of tert-butyl(3R)-3-({[6-(4-cyanophenyl)-5-(4-methylphenyl)[1,2,4]triazolo[4,3-a]pyridin-8-yl]oxy}methyl)pyrrolidine-1-carboxylate(83.4 mg, 0.16 mmol) in methylene chloride (2.0 mL) at 0° C. was addedtrifluoroacetic acid (0.4 mL, 5 mmol). The reaction mixture was stirredat 0° C. for 1.5 h, and then concentrated. The residue was purified viapreparative HPLC (pH=2, MeCN/water with TFA) to give the product as awhite solid (TFA salt). LC/MS calculated for C₂₅H₂₄N₅O [M+H]⁺:m/z=410.2; found 410.2.

Example 22-fluoro-4-{5-(4-methylphenyl)-8-[(3R)-pyrrolidin-3-ylmethoxy][1,2,4]triazolo[4,3-a]pyridin-6-yl}benzonitrile

A mixture of (4-cyano-3-fluorophenyl)boronic acid (22.3 mg, 0.14 mmol),tert-butyl(3R)-3-({[6-chloro-5-(4-methylphenyl)[1,2,4]triazolo[4,3-a]pyridin-8-yl]oxy}methyl)pyrrolidine-1-carboxylate(Example 1, Step 4, 30.0 mg, 0.0677 mmol), sodium carbonate (14.4 mg,0.135 mmol), and[1,1′-bis(di-cyclohexylphosphino)ferrocene]-dichloropalladium(II) (5.1mg, 0.0068 mmol) in tert-butyl alcohol (0.70 mL) and water (0.70 mL) wasfirst purged with nitrogen, and then stirred and heated at 100° C. for1.5 h. The resulting mixture was cooled to room temperature, quenchedwith water, and extracted with EtOAc. The combined extracts were driedover Na₂SO₄, and concentrated. The residue was dissolved in methylenechloride (1.5 mL) at 0° C., and trifluoroacetic acid (0.3 mL, 4 mmol)was added. The reaction mixture was stirred at 0° C. for 1 h, and thenconcentrated. The residue was purified via preparative HPLC (pH=2,MeCN/water with TFA) to give the product as a white solid (TFA salt).LC/MS calculated for C₂₅H₂₃FN₅O [M+H]⁺: m/z=428.2; found 428.2.

Example 34-{5-(4-methylphenyl)-3-oxo-8-[(3R)-pyrrolidin-3-ylmethoxy]-2,3-dihydro[1,2,4]triazolo[4,3-a]pyridin-6-yl})benzonitrile

Step 1: tert-butyl(3R)-3-({[6-chloro-5-(4-methylphenyl)-3-oxo-2,3-dihydro[1,2,4]triazolo[4,3-a]pyridin-8-yl]oxy}methyl)pyrrolidine-1-carboxylate

To a solution of tert-butyl(3R)-3-({[2,5-dichloro-6-(4-methylphenyl)pyridin-3-yl]oxy}methyl)pyrrolidine-1-carboxylate(Example 1, Step 2: 646.2 mg, 1.48 mmol) in isopropyl alcohol (4.0 mL)was added hydrazine hydrate (4.0 mL, 82 mmol). The resulting mixture washeated at 130° C. for 2 h under microwave conditions. The resultingmixture was cooled to room temperature, and then concentrated to give awhite solid. This solid was then dissolved in tetrahydrofuran (10.0 mL)and N,N-carbonyldiimidazole (359 mg, 2.22 mmol) was added. The reactionmixture was stirred at room temperature overnight and concentrated. Theresidue was purified via column chromatography (0% to 15% methanol inDCM) to give the product as a white solid (470 mg, 69%). LC/MScalculated for C₂₃H₂₈ClN₄O₄[M+H]⁺: m/z=459.2; found 459.2.

Step 2: tert-butyl(3R)-3-({[6-(4-cyanophenyl)-5-(4-methylphenyl)-3-oxo-2,3-dihydro[1,2,4]triazolo[4,3-a]pyridin-8-yl]oxy}methyl)pyrrolidine-1-carboxylate

A mixture of (4-cyanophenyl)boronic acid (27.2 mg, 0.19 mmol),tert-butyl(3R)-3-({[6-chloro-5-(4-methylphenyl)-3-oxo-2,3-dihydro[1,2,4]triazolo[4,3-a]pyridin-8-yl]oxy}methyl)pyrrolidine-1-carboxylate(42.5 mg, 0.093 mmol), sodium carbonate (19.6 mg, 0.19 mmol), and[1,1′-bis(di-cyclohexylphosphino)ferrocene]-dichloropalladium(II) (7.0mg, 0.0092 mmol) in tert-butyl alcohol (1.2 mL) and water (1.2 mL) waspurged with nitrogen, then stirred and heated at 95° C. for 1.5 h. Theresulting mixture was cooled to room temperature, and diluted with waterthen extracted with EtOAc. The combined extracts were dried over Na₂SO₄,and concentrated. The residue was purified via column chromatography (0%to 15% methanol in DCM) to give the product as a yellow oil. LC/MScalculated for C₃₀H₃₂N₅O₄ [M+H]⁺: m/z=526.2; found 526.2.

Step 3:4-{5-(4-methylphenyl)-3-oxo-8-[(3R)-pyrrolidin-3-ylmethoxy]-2,3-dihydro[1,2,4]triazolo[4,3-a]pyridin-6-yl}benzonitrile

To a solution of tert-butyl(3R)-3-({[6-(4-cyanophenyl)-5-(4-methylphenyl)-3-oxo-2,3-dihydro[1,2,4]triazolo[4,3-a]pyridin-8-yl]oxy}methyl)pyrrolidine-1-carboxylate(66.7 mg, 0.13 mmol) in methylene chloride (2.0 mL) at 0° C. was addedtrifluoroacetic acid (0.4 mL, 5 mmol). The reaction mixture was stirredat 0° C. for 1 h and concentrated. The residue was purified viapreparative HPLC (pH=2, MeCN/water with TFA) to give the product as awhite solid (TFA salt). LC/MS calculated for C₂₅H₂₄N₅O₂ [M+H]⁺:m/z=426.2; found 426.1.

Example 44-{2-methyl-5-(4-methylphenyl)-3-oxo-8-[(3R)-pyrrolidin-3-ylmethoxy]-2,3-dihydro[1,2,4]triazolo[4,3-a]pyridin-6-yl}benzonitrile

To a solution of tert-butyl(3R)-3-({[6-(4-cyanophenyl)-5-(4-methylphenyl)-3-oxo-2,3-dihydro[1,2,4]triazolo[4,3-a]pyridin-8-yl]oxy}methyl)pyrrolidine-1-carboxylate(Example 3, Step 2: 45 mg, 0.086 mmol) and potassium carbonate (95 mg,0.69 mmol) in N,N-dimethylformamide (1.5 mL) at room temperature wasadded methyl iodide (32 μL, 0.52 mmol). The reaction mixture was stirredat room temperature for 3 h and then filtered and washed with DCM. Thefiltrate was concentrated and the residue was purified via columnchromatography (0% to 75% EtOAc in hexanes) to give a colorless oil.This intermediate was then dissolved in methylene chloride (1.5 mL) at0° C., and trifluoroacetic acid (0.3 mL, 4 mmol) was added. The mixturewas stirred at 0° C. for 1 h and concentrated. The residue was purifiedvia preparative HPLC (pH=2, MeCN/water with TFA) to give the product asa white solid (TFA salt). LC/MS calculated for C₂₆H₂₆N₅O₂ [M+H]⁺:m/z=440.2; found 440.2.

Example 5(R)-4-(2-(cyanomethyl)-3-oxo-8-(pyrrolidin-3-ylmethoxy)-5-p-tolyl-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-6-yl)benzonitrile

A procedure analogous to that of Example 4 was followed withbromoacetonitrile replacing methyl iodide to afford the product as ayellow solid (TFA salt). LC-MS calculated for C₂₇H₂₅N₆O₂ [M+H]⁺:m/z=465.2; found 465.2.

Example 64-{2-(2-cyanoethyl)-5-(4-methylphenyl)-3-oxo-8-[(3R)-pyrrolidin-3-ylmethoxy]-2,3-dihydro[1,2,4]triazolo[4,3-a]pyridin-6-yl})benzonitrile

A procedure analogous to that of Example 4 was followed with3-bromo-propanenitrile replacing methyl iodide to afford the product asa yellow solid (TFA salt). LC-MS calculated for C₂₈H₂₇N₆O₂ [M+H]⁺:m/z=479.2; found 479.3.

Example 74-{2-(cyclopentylmethyl)-5-(4-methylphenyl)-3-oxo-8-[(3R)-pyrrolidin-3-ylmethoxy]-2,3-dihydro[1,2,4]triazolo[4,3-a]pyridin-6-yl})benzonitrile

A procedure analogous to that of Example 4 was followed with(bromomethyl)cyclopentane replacing methyl iodide to afford the productas a white solid (TFA salt). LC/MS calculated for C₃₁H₃₄N₅O₂ [M+H]⁺:m/z=508.3; found 508.3.

Example 84-[5-(4-methylphenyl)-3-oxo-8-[(3R)-pyrrolidin-3-ylmethoxy]-2-(tetrahydrofuran-2-ylmethyl)-2,3-dihydro[1,2,4]triazolo[4,3-a]pyridin-6-yl]benzonitrile

A procedure analogous to that of Example 4 was followed withtetrahydrofurfuryl bromide replacing methyl iodide to afford the productas a white solid (TFA salt). LC-MS calculated for C₃₀H₃₂N₅O₃ [M+H]⁺:m/z=510.2; found 510.2.

Example 94-{5-(4-methylphenyl)-2-[(1-methyl-1H-pyrazol-3-yl)methyl]-3-oxo-8-[(3R)-pyrrolidin-3-ylmethoxy]-2,3-dihydro[1,2,4]triazolo[4,3-a]pyridin-6-yl}benzonitrile

A procedure analogous to that of Example 4 was followed with3-(chloromethyl)-1-methyl-1H-pyrazole replacing methyl iodide to affordthe product as a white solid (TFA salt). LC-MS calculated for C₃₀H₃₀N₇O₂[M+H]⁺: m/z=520.2; found 520.3.

Example 104-{5-(4-methylphenyl)-2-(2-morpholin-4-ylethyl)-3-oxo-8-[(3R)-pyrrolidin-3-ylmethoxy]-2,3-dihydro[1,2,4]triazolo[4,3-a]pyridin-6-yl}benzonitrile

A procedure analogous to that of Example 4 was followed with4-(2-bromoethyl)morpholine hydrochloride replacing methyl iodide toafford the product as a white solid (TFA salt). LC-MS calculated forC₃₁H₃₅N₆O₃ [M+H]⁺: m/z=539.3; found 539.4.

Example 112-[6-(4-cyanophenyl)-5-(4-methylphenyl)-3-oxo-8-[(3R)-pyrrolidin-3-ylmethoxy][1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl]acetamide

A procedure analogous to that of Example 4 was followed with2-bromoacetamide replacing methyl iodide to afford the product as awhite solid (TFA salt). LC-MS calculated for C₂₇H₂₇N₆O₃ [M+H]⁺:m/z=483.2; found 483.1.

Example 124-[5-(4-methylphenyl)-3-oxo-8-[(3R)-pyrrolidin-3-ylmethoxy]-2-(3,3,3-trifluoro-2-hydroxypropyl)-2,3-dihydro[1,2,4]triazolo[4,3-a]pyridin-6-yl]benzonitrile

A procedure analogous to that of Example 4 was followed with3-bromo-1,1,1-trifluoropropan-2-ol replacing methyl iodide to afford theproduct as a white solid (TFA salt). LC-MS calculated for C₂₈H₂₇F₃N₅O₃[M+H]⁺: m/z=538.2; found 538.3.

Example 134-{5-(4-methylphenyl)-3-oxo-2-(piperidin-4-ylmethyl)-8-[(3R)-pyrrolidin-3-ylmethoxy]-2,3-dihydro[1,2,4]triazolo[4,3-a]pyridin-6-yl})benzonitrile

A procedure analogous to that of Example 4 was followed withtert-butyl-4-(bromomethyl)piperidine-1-carboxylate replacing methyliodide to afford the product as a white solid (TFA salt). LC-MScalculated for C₃₁H₃₅N₆O₂ [M+H]⁺: m/z=523.3; found 523.2.

Example 144-{5-(4-methylphenyl)-3-oxo-2-(2-phenoxyethyl)-8-[(3R)-pyrrolidin-3-ylmethoxy]-2,3-dihydro[1,2,4]triazolo[4,3-a]pyridin-6-yl})benzonitrile

A procedure analogous to that of Example 4 was followed with(2-bromoethoxy)-benzene replacing methyl iodide to afford the product asa white solid (TFA salt). LC-MS calculated for C₃₃H₃₂N₅O₃ [M+H]⁺:m/z=546.2; found 546.1.

Example 154-{2-[2-(dimethylamino)ethyl]-5-(4-methylphenyl)-3-oxo-8-[(3R)-pyrrolidin-3-ylmethoxy]-2,3-dihydro[1,2,4]triazolo[4,3-a]pyridin-6-yl}benzonitrile

A procedure analogous to that of Example 4 was followed with2-bromo-N,N-dimethylethanamine hydrobromide replacing methyl iodide toafford the product as a white solid (TFA salt). LC-MS calculated forC₂₉H₃₃N₆O₂ [M+H]⁺: m/z=497.3; found 497.2.

Example 164-{2-benzyl-5-(4-methylphenyl)-3-oxo-8-[(3R)-pyrrolidin-3-ylmethoxy]-2,3-dihydro[1,2,4]triazolo[4,3-a]pyridin-6-yl})benzonitrile

Step 1: tert-butyl(3R)-3-({[2-benzyl-6-chloro-5-(4-methylphenyl)-3-oxo-2,3-dihydro[1,2,4]triazolo[4,3-a]pyridin-8-yl]oxy}methyl)pyrrolidine-1-carboxylate

To a solution of tert-butyl(3R)-3-({[6-chloro-5-(4-methylphenyl)-3-oxo-2,3-dihydro[1,2,4]triazolo[4,3-a]pyridin-8-yl]oxy}methyl)pyrrolidine-1-carboxylate(Example 3, Step 1, 35.0 mg, 0.076 mmol) and potassium carbonate (84 mg,0.61 mmol) in N,N-dimethylformamide (1.5 mL) was added benzyl bromide(45 μL, 0.38 mmol). The reaction mixture was stirred at room temperaturefor 3 h and then filtered, washed with EtOAc. The filtrate wasconcentrated and the residue was purified via column chromatography (25%to 55% EtOAc in hexanes) to give the product as a slightly yellow oil(29.7 mg, 71%). LC/MS calculated for C₃₀H₃₄ClN₄O₄[M+H]⁺: m/z=549.2;found 549.2.

Step 2:4-{2-benzyl-5-(4-methylphenyl)-3-oxo-8-[(3R)-pyrrolidin-3-ylmethoxy]-2,3-dihydro[1,2,4]triazolo[4,3-a]pyridin-6-yl}benzonitrile

A mixture of (4-cyanophenyl)boronic acid (15.9 mg, 0.108 mmol),tert-butyl(3R)-3-({[2-benzyl-6-chloro-5-(4-methylphenyl)-3-oxo-2,3-dihydro[1,2,4]triazolo[4,3-a]pyridin-8-yl]oxy}methyl)pyrrolidine-1-carboxylate(29.7 mg, 0.0541 mmol), sodium carbonate (11.5 mg, 0.108 mmol), and[1,1′-bis-(di-tert-butylphosphino)ferrocene]dichloropalladium (II) (5.3mg, 0.0081 mmol) in 1,4-dioxane (1.0 mL) and water (0.1 mL) was purgedwith nitrogen, then stirred and heated at 110° C. for 3 h. The resultingmixture was cooled to room temperature, diluted with EtOAc, filteredthen dried over Na₂SO₄ and concentrated. The residue was dissolved inmethylene chloride (1.5 mL) at 0° C. and trifluoroacetic acid (0.3 mL, 4mmol) was added. The reaction mixture was stirred at 0° C. for 1 h, andconcentrated. The residue was purified preparative HPLC (pH=2,MeCN/water with TFA) to give the product as a white solid (TFA salt).LC/MS calculated for C₃₂H₃₀N₅O₂ [M+H]⁺: m/z=516.2; found 516.3.

Example 174-{2-(4-cyanobenzyl)-5-(4-methylphenyl)-3-oxo-8-[(3R)-pyrrolidin-3-ylmethoxy]-2,3-dihydro[1,2,4]triazolo[4,3-a]pyridin-6-yl})benzonitrile

A procedure analogous to that of Example 16 was followed withp-cyanobenzyl bromide replacing benzyl bromide in Step 1 to afford theproduct as a yellow solid (TFA salt). LC-MS calculated for C₃₃H₂₉N₆O₂[M+H]⁺: m/z=541.2; found 541.2.

Example 184-{2-(2-hydroxyethyl)-5-(4-methylphenyl)-3-oxo-8-[(3R)-pyrrolidin-3-ylmethoxy]-2,3-dihydro[1,2,4]triazolo[4,3-a]pyridin-6-yl})benzonitrile

A procedure analogous to that of Example 16 was followed with2-bromoethanol replacing benzyl bromide in Step 1 to afford the productas a white solid (TFA salt). LC/MS calculated for C₂₇H₂₈N₅O₃ [M+H]⁺:m/z=470.2; found 470.2.

Example 194-{5-(4-methylphenyl)-8-[(3R)-pyrrolidin-3-ylmethoxy][1,2,4]triazolo[4,3-a]pyrazin-6-yl}benzonitrile

Step 1: 5-bromo-6-chloropyrazin-2-ol

To a solution of 5-bromo-6-chloropyrazin-2-amine (Accela ChemBio, cat#SY008157 350 mg, 1.7 mmol) in concentrated sulfuric acid (3.0 mL) at 0°C. was added sodium nitrite (120 mg, 1.7 mmol) portionwise. The reactionmixture was stirred at 0° C. for 1 h then poured into ice. The resultingsolid was collected by filtration, and washed with water and hexanesthen dried to give the product as a pale yellow solid (263 mg, 75%).LC/MS calculated for C₄H₃BrClN₂O [M+H]⁺: m/z=208.9; found 208.9.

Step 2: 6-chloro-5-(4-methylphenyl) pyrazin-2-ol

A mixture of 5-bromo-6-chloropyrazin-2-ol (263 mg, 1.26 mmol), palladiumacetate (28.2 mg, 0.13 mmol), tri-o-tolylphosphine (76.6 mg, 0.25 mmol),sodium carbonate (333 mg, 3.14 mmol), and (4-methylphenyl)boronic acid(188 mg, 1.38 mmol) in 1,2-dimethoxyethane (10 mL) and water (2 mL) wasfirst purged with nitrogen and then stirred and heated at 85° C. for 2h. The reaction mixture was cooled to room temperature, passed through apad of Celite, rinsed with EtOAc and the filtrate was concentrated. Theresidue was purified via column chromatography (0% to 15% methanol inDCM) to give the product as a yellow solid (181 mg, 65%). LC/MScalculated for C₁₁H₁₀ClN₂O [M+H]⁺: m/z=221.0; found 221.1.

Step 3: 4-[6-hydroxy-3-(4-methylphenyl)pyrazin-2-yl]benzonitrile

A mixture of (4-cyanophenyl)boronic acid (240 mg, 1.64 mmol),6-chloro-5-(4-methylphenyl)pyrazin-2-ol (180.5 mg, 0.82 mmol), sodiumcarbonate (173 mg, 1.63 mmol), and[1,1′-bis(di-cyclohexylphosphino)ferrocene]-dichloropalladium(II) (50mg, 0.06 mmol) in tert-butyl alcohol (3.0 mL) and water (3.0 mL) wasfirst purged with nitrogen, then stirred and heated at 100° C. for 1.5h. The resulting mixture was cooled to room temperature, diluted withwater, and extracted with EtOAc. The combined extracts were dried overNa₂SO₄, and concentrated. The residue was purified via columnchromatography (0% to 15% methanol in DCM) to give the product as ayellow solid (230 mg, 98%). LC/MS calculated for C₁₈H₁₄N₃O [M+H]⁺:m/z=288.1; found 288.1.

Step 4: tert-butyl(3R)-3-({[6-(4-cyanophenyl)-5-(4-methylphenyl)pyrazin-2-yl]oxy}methyl)pyrrolidine-1-carboxylate

To a solution of4-[6-hydroxy-3-(4-methylphenyl)pyrazin-2-yl]benzonitrile (230 mg, 0.80mmol), tert-butyl (3R)-3-(hydroxymethyl)pyrrolidine-1-carboxylate (323mg, 1.60 mmol), and triphenylphosphine (421 mg, 1.60 mmol) intetrahydrofuran (6.0 mL) was added diethyl azodicarboxylate (40 wt. % intoluene, 0.729 mL, 1.85 mmol) dropwise. The reaction mixture was stirredat room temperature for 2 h and concentrated. The residue was purifiedvia column chromatography (0% to 75% EtOAc in Hexanes) to give theproduct as a yellow oil (216 mg, 57%). LC/MS calculated for C₂₄H₂₃N₄O₃[M-^(t)Bu+2H]⁺: m/z=415.2; found 415.2.

Step 5: tert-butyl(3R)-3-({[3-chloro-6-(4-cyanophenyl)-5-(4-methylphenyl)pyrazin-2-yl]oxy}methyl)pyrrolidine-1-carboxylate

To a solution of tert-butyl(3R)-3-({[6-(4-cyanophenyl)-5-(4-methylphenyl)pyrazin-2-yl]oxy}methyl)pyrrolidine-1-carboxylate(24.5 mg, 0.052 mmol) in methylene chloride (1.5 mL) at room temperaturewas added m-chloroperbenzoic acid (35.9 mg, 0.21 mmol). The resultingmixture was stirred at 35° C. overnight then cooled to room temperatureand concentrated. The residue was purified via column chromatography (0to 15% methanol in DCM) to give the desired intermediate. Thisintermediate was then dissolved in toluene (0.6 mL) andN,N-dimethylformamide (0.6 mL) at 0° C., and phosphoryl chloride (24.3μL, 0.26 mmol) was added. The reaction mixture was stirred and graduallywarmed to room temperature over 2 h. The resulting mixture was quenchedwith saturated NaHCO₃ (aq) solution, and extracted with EtOAc. Thecombined extracts were dried over Na₂SO₄, and concentrated. The residuewas purified via column chromatography (15% to 55% EtOAc in hexanes) togive the product as a slightly yellow solid, which was used directly inthe next step. LC/MS calculated for C₂₄H₂₂ClN₄O₃[M-^(t)Bu+2H]⁺:m/z=449.1; found 449.1.

Step 6: tert-butyl(3R)-3-({[6-(4-cyanophenyl)-3-hydrazino-5-(4-methylphenyl)pyrazin-2-yl]oxy}methyl)pyrrolidine-1-carboxylate

The product from Step 5 was dissolved in hydrazine hydrate (0.75 mL) andisopropyl alcohol (0.75 mL). The resulting mixture was then heated at130° C. under microwave conditions for 1 h. The reaction mixture wascooled to room temperature, diluted with methanol, and concentrated togive the crude product, which was used directly in the next step. LC/MScalculated for C₂₈H₃₃N₆O₃ [M+H]⁺: m/z=501.3; found 501.2.

Step 7:4-{5-(4-methylphenyl)-8-[(3R)-pyrrolidin-3-ylmethoxy][1,2,4]triazolo[4,3-a]pyrazin-6-yl}benzonitrile

The product from Step 6 was dissolved in ethyl orthoformate (1.5 mL) andheated to 105° C. for 1 h until. The reaction mixture was cooled to roomtemperature and concentrated. The residue was dissolved in methylenechloride (1.5 mL) at 0° C. and trifluoroacetic acid (0.3 mL, 4 mmol) wasadded. The resulting mixture was stirred at 0° C. for 1 h andconcentrated. The residue was purified via preparative HPLC (pH=2,MeCN/water with TFA) to give the product as a white solid (TFA salt).LC/MS calculated for C₂₄H₂₃N₆O [M+H]⁺: m/z=411.2; found 411.2.

Example 204-{5-(4-methylphenyl)-3-oxo-8-[(3R)-pyrrolidin-3-ylmethoxy]-2,3-dihydro[1,2,4]triazolo[4,3-a]pyrazin-6-yl}benzonitrile

To a solution of tert-butyl(3R)-3-({[3-chloro-6-(4-cyanophenyl)-5-(4-methylphenyl)-pyrazin-2-yl]oxy}methyl)pyrrolidine-1-carboxylate(Example 19, Step 5: 44.5 mg, 0.088 mmol) in isopropyl alcohol (1.0 mL)was added hydrazine hydrate (1.00 mL, 20.6 mmol). The resulting mixturewas heated at 110° C. for 30 min under microwave conditions. Theresulting mixture was cooled to room temperature, diluted with methanol,and concentrated. The residue was dissolved in tetrahydrofuran (1.5 mL)and N,N-carbonyldiimidazole (42.9 mg, 0.26 mmol) was added. Theresulting mixture was stirred at room temperature overnight, then at 45°C. for 3 h until completion of the reaction. The resulting mixture wasconcentrated, and dissolved in methylene chloride (1.5 mL) at 0° C., andtrifluoroacetic acid (0.30 mL, 3.9 mmol) was added. The reaction mixturewas stirred at 0° C. for 1 h and concentrated. The residue was purifiedvia preparative HPLC (pH=2, MeCN/water with TFA) to give the product asa slightly yellow solid (TFA salt). LC/MS calculated for C₂₄H₂₃N₆O₂[M+H]⁺: m/z=427.2; found 427.1.

Example A: LSD1 Histone Demethylase Biochemical Assay

LANCE LSD1/KDM1A demethylase assay-10 μL of 1 nM LSD-1 enzyme (ENZOBML-SE544-0050) in the assay buffer (50 mM Tris, pH 7.5, 0.01% Tween-20,25 mM NaCl, 5 mM DTT) were preincubated for 1 hour at 25° C. with 0.8 μLcompound/DMSO dotted in black 384 well polystyrene plates. Reactionswere started by addition of 10 μL of assay buffer containing 0.4 μMBiotin-labeled Histone H3 peptide substrate:ART-K(Mel)-QTARKSTGGKAPRKQLA-GGK(Biotin) SEQ ID NO: 1 (AnaSpec 64355)and incubated for 1 hour at 25° C. Reactions were stopped by addition of10 μL 1× LANCE Detection Buffer (PerkinElmer CR97-100) supplemented with1.5 nM Eu-anti-unmodified H3K4 Antibody (PerkinElmer TRF0404), and 225nM LANCE Ultra Streptavidin (PerkinElmer TRF102) along with 0.9 mMTranylcypromine-HCl (Millipore 616431). After stopping the reactionsplates were incubated for 30 minutes and read on a PHERAstar FS platereader (BMG Labtech). IC₅₀ data for the example compounds is provided inTable 1 (+ refers to IC₅₀<50 nM; ++ refers to IC₅₀>50 nM and ≦100 nM;+++ refers to IC₅₀>100 nM and ≦500 nM; ++++ refers to IC₅₀>500 nM and≦1000 nM).

TABLE 1 Example No. IC₅₀ (nM) 1 + 2 + 3 + 4 +++ 5 + 6 + 7 + 8 ++ 9 ++ 10++ 11 ++ 12 ++ 13 + 14 + 15 + 16 + 17 + 18 ++ 19 ++ 20 ++

Various modifications of the invention, in addition to those describedherein, will be apparent to those skilled in the art from the foregoingdescription. Such modifications are also intended to fall within thescope of the appended claims. Each reference, including all patent,patent applications, and publications, cited in the present applicationis incorporated herein by reference in its entirety.

1-40. (canceled)
 41. A method of treating cancer comprisingadministering to a patient a therapeutically effective amount of acompound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein: X is N orCR^(X); Y is (a) C═O and Z is NR^(Z) or (b) Y is CR³ and Z is N; whereinthe bond between Y and Z represented by

is a single bond in the case of (a) and a double bond in the case of(b); Ring A is C₆₋₁₀ aryl or 5-10 membered heteroaryl comprising carbonand 1, 2, 3, or 4 heteroatoms selected from N, O, and S, wherein saidC₆₋₁₀ aryl and 5-10 membered heteroaryl are each optionally substitutedby 1, 2, 3, or 4 substituents independently selected from R^(A); Ring Bis C₆₋₁₀ aryl; 5-10 membered heteroaryl comprising carbon and 1, 2, 3 or4 heteroatoms selected from N, O, and S; C₃₋₁₀ cycloalkyl; or 4-10membered heterocycloalkyl comprising carbon and 1, 2, 3 or 4 heteroatomsselected from N, O, and S; wherein said C₆₋₁₀ aryl, 5-10 memberedheteroaryl, C₃₋₁₀ cycloalkyl, and 4-10 membered heterocycloalkyl areeach optionally substituted by 1, 2, 3, or 4 substituents independentlyselected from R^(B); R¹ is halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl, Cy¹, CN, OR^(a1), SR^(a1), C(O)R^(b1),C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1), OC(O)NR^(c1)R^(d1),NR^(c1)R^(d1), NR^(c1)C(O)R^(b1), NR^(c1)C(O)OR^(a1),NR^(c1)C(O)NR^(c1)R^(d1), C(═NR^(e1))R^(b1), C(═NR^(e1))NR^(c1)R^(d1),NR^(c1)C(═NR^(e1))NR^(c1)R^(d1), NR^(c1)S(O)R^(b1), NR^(c1)S(O)₂R^(b1),NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1),or S(O)₂NR^(c1)R^(d1), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl are each optionally substituted with 1, 2, or 3 substituentsindependently selected from Cy¹, halo, CN, OR^(a1), SR^(a1), C(O)R^(b1),C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1), OC(O)NR^(c1)R^(d1),NR^(c1)R^(d1), NR^(c1)C(o)R^(b1), NR^(c1)C(O)OR^(a1),NR^(c1)C(O)NR^(c1)R^(d1), C(═NR^(e1))R^(b1), C(═NR^(e1))NR^(c1)R^(d1),NR^(c1)C(═NR^(e1))NR^(c1)R^(d1), NR^(c1)S(O)R^(b1), NR^(c1)S(O)₂R^(b1),NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1),and S(O)₂NR^(c1)R^(d1); R³ is H, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, Cy², CN, OR^(a2), SR^(a2), C(O)R^(b2),C(O)NR^(c2)R^(d2), C(O)OR^(a2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)OR^(a2), NR^(c2)C(O)NR^(c2)R^(d2), C(═NR^(e2))R^(b2),C(═NR^(e2))NR^(c2)R^(d2), NR^(c2)C(═NR^(e2))NR^(c2)R^(d2)NR^(c2)S(O)R^(b2), NR^(c2)S(O)₂R^(b2), NR^(c2)S(O)₂NR^(c2)R^(d2),S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2), or S(O)₂NR^(c2)R^(d2),wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are eachoptionally substituted with 1, 2, or 3 substituents independentlyselected from Cy², halo, CN, OR^(a2), SR^(a2), C(O)R^(b2),C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2), OC(O)NR^(c2)R^(d2),NR^(c2)R^(d2), NR^(c2)C(O)R^(b2), NR^(c2)C(O)OR^(a2),NR^(c2)C(O)NR^(c2)R^(d2), C(═NR^(e2))R^(b2), C(═NR^(e2))NR^(c2)R^(d2),NR^(c2)C(═NR^(e2))NR^(c2)R^(d2), NR^(c2)S(O)R^(b2), NR^(c2)S(O)₂R^(b2),NR^(c2)S(O)₂NR^(c2)R^(d2), S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2),and S(O)₂NR^(c2)R^(d2); each R^(A) is independently selected from halo,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, CN, NO₂,OR^(a4), SR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4),OC(O)R^(b4), OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),NR^(c4)C(O)OR^(a4), NR^(c4)C(O)NR^(c4)R^(d4), C(═NR^(e4))R^(b4),C(═NR^(e4))NR^(c4)R^(d4), NR^(c4)C(═NR^(e4))NR^(c4)R^(d4),NR^(c4)S(O)R^(b4), NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4),S(O)R^(b4), S(O)NR^(c4)R^(d4), S(O)₂R^(b4), and S(O)₂NR^(c4)R^(d4),wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are eachoptionally substituted by 1, 2, or 3, substituents independentlyselected from halo, C₁₋₆ haloalkyl, CN, NO₂, OR^(a4), SR^(a4),C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4),OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),NR^(c4)C(O)OR^(a4), NR^(c4)C(O)NR^(c4)R^(d4), C(═NR^(e4))R^(b4),C(═NR^(e4))NR^(c4)R^(d4), NR^(c4)C(═NR^(e4))NR^(c4)R^(d4)NR^(c4)S(O)R^(b4), NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4),S(O)R^(b4), S(O)NR^(c4)R^(d4), S(O)₂R^(b4), and S(O)₂NR^(c4)R^(d4); eachR^(B) is independently selected from Cy³, halo, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, CN, NO₂, OR^(a5), SR^(a5),C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5),OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5), NR^(c5)C(O)R^(b5),NR^(c5)C(O)OR^(a5), NR^(c5)C(O)NR^(c5)R^(d5), C(═NR^(e5))R^(b5),C(═NR^(e5))NR^(c5)R^(d5), NR^(c5)C(═NR^(e5))NR^(c5)R^(d5),NR^(c5)S(O)R^(b5), NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5),S(O)R^(b5), S(O)NR^(c5)R^(d5), S(O)₂R^(b5), and S(O)₂NR^(c5)R^(d5),wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are eachoptionally substituted by 1, 2, or 3 substituents independently selectedfrom Cy³, halo, C₁₋₆ haloalkyl, CN, NO₂, OR^(a5), SR^(a5), C(O)R^(b5),C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5), OC(O)NR^(c5)R^(d5),NR^(c5)R^(d5), NR^(c5)C(O)R^(b5), NR^(c5)C(O)OR^(a5),NR^(c5)C(O)NR^(c5)R^(d5), C(═NR^(e5))R^(b5), C(═NR^(e5))NR^(c5)R^(d5),NR^(c5)C(═NR^(e5))NR^(c5)R^(d5), NR^(c5)S(O)R^(b5), NR^(c5)S(O)₂R^(b5),NR^(c5)S(O)₂NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5), S(O)₂R^(b5),and S(O)₂NR^(c5)R^(d5); R^(X) is H, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, CN, OR^(a8), SR^(a8), C(O)R^(b8),C(O)NR^(c8)R^(d8), C(O)OR^(a8), OC(O)R^(b8), OC(O)NR^(c8)R^(d8),NR^(c8)R^(d8), NR^(c8)C(O)R^(b8), NR^(c8)C(O)OR^(a8),NR^(c8)C(O)NR^(c8)R^(d8), C(═NR^(e8))R^(b8), C(═NR^(e8))NR^(c8)R^(d8),NR^(c8)C(═NR^(e8))NR^(c8)R^(d8), NR^(c8)S(O)R^(b8), NR^(c8)S(O)₂R^(b8),NR^(c8)S(O)₂NR^(c8)R^(d8), S(O)R^(b8), S(O)NR^(c8)R^(d8), S(O)₂R^(b8),or S(O)₂NR^(c8)R^(d8); R^(Z) is H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, or Cy⁴, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,and C₂₋₆ alkynyl are each optionally substituted with 1, 2, 3, 4, or 5substituents independently selected from Cy⁴, halo, CN, OR^(a3),SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3), OC(O)R^(b3),OC(O)NR^(c3)R^(d3), NR^(c3)R^(d3), NR^(c3)C(O)R^(b3),NR^(c3)C(O)OR^(a3), NR^(c3)C(O)NR^(c3)R^(d3), C(═NR^(e3))R^(b3),C(═NR^(e3))NR^(c3)R^(d3), NR^(c3)C(═NR^(e3))NR^(c3)R^(d3),NR^(c3)S(O)R^(b3), NR^(c3)S(O)₂R^(b3), NR^(c3) S(O)₂NR^(c3)R^(d3),S(O)R^(b3), S(O)NR^(c3)R^(d3), S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3); eachCy¹, Cy², Cy³, Cy⁴, and Cy⁵ is independently selected from C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, and 4-10 memberedheterocycloalkyl, each of which is optionally substituted with 1, 2, 3,or 4 substituents independently selected from R^(Cy); each R^(Cy) isselected from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl,4-7 membered heterocycloalkyl, phenyl-C₁₋₄ alkyl-, C₃₋₇ cycloalkyl-C₁₋₄alkyl-, (5-6 membered heteroaryl)-C₁₋₄ alkyl-, (4-7 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a6), SR^(a6), C(O)R^(b6),C(O)NR^(c6)R^(d6), C(O)OR^(a6), OC(O)R^(b6), OC(O)NR^(c6)R^(d6),C(═NR^(e6))NR^(c6)R^(d6), NR^(c6)C(═NR^(e6))NR^(c6)R^(d6),NR^(c6)R^(d6), NR^(c6)C(O)R^(b6), NR^(c6)C(O)OR^(a6),NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)S(O)R^(b6), NR^(c6)S(O)₂R^(b6),NR^(c6)S(O)₂NR^(c6)R^(d6), S(O)R^(b6), S(O)NR^(c6)R^(d6), S(O)₂R^(b6),and S(O)₂NR^(c6)R^(d6), wherein said C₁₋₄ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7 memberedheterocycloalkyl, phenyl-C₁₋₄ alkyl-, C₃₋₇ cycloalkyl-C₁₋₄ alkyl-, (5-6membered heteroaryl)-C₁₋₄ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₄ alkyl- are each optionally substituted by 1, 2,or 3 substituents independently selected from C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄ cyanoalkyl, halo, CN, NO₂, OR^(a6), SR^(a6), C(O)R^(b6),C(O)NR^(c6)R^(d6), C(O)OR^(a6), OC(O)R^(b6), OC(O)NR^(c6)R^(d6),C(═NR^(e6))NR^(c6)R^(d6), NR^(c6)C(═NR^(e6))NR^(c6)R^(d6),NR^(c6)R^(d6), NR^(c6)C(O)R^(b6), NR^(c6)C(O)OR^(a6),NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)S(O)R^(b6), NR^(c6)S(O)₂R^(b6),NR^(c6)S(O)₂NR^(c6)R^(d6), S(O)R^(b6), S(O)NR^(c6)R^(d6), S(O)₂R^(b6),and S(O)₂NR^(c6)R^(d6); each R^(a1) is independently selected from H,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and Cy⁵, wherein said C₁₋₆alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are each optionally substitutedwith 1, 2, or 3 substituents independently selected from Cy⁵, halo, CN,OR^(a7), SR^(a7), C(O)R^(b7), C(O)NR^(c7)R^(d7), C(O)OR^(a7),OC(O)R^(b7), OC(O)NR^(c7)R^(d7), NR^(c7)R^(d7), NR^(c7)C(O)R^(b7),NR^(c7)C(O)OR^(a7), NR^(c7)C(O)NR^(c7)R^(d7), C(═NR^(e7))R^(b7),C(═NR^(e7))NR^(c7)R^(d7), NR^(c7)C(═NR^(e7))NR^(c7)R^(d7),NR^(c7)S(O)R^(b7), NR^(c7)S(O)₂R^(b7), NR⁷S(O)₂NR^(c7)R^(d7),S(O)R^(b7), S(O)NR^(c7)R^(d7), S(O)₂R^(b7), and S(O)₂NR^(c7)R^(d7); eachR^(b1), R^(c1), and R^(d1) is independently selected from H, C₁₋₆ alkyl,C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄alkyl-, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- are each optionally substituted with 1, 2,3, 4, or 5 substituents independently selected from C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄ cyanoalkyl, halo, CN, OR^(a8), SR^(a8), C(O)R^(b8),C(O)NR^(c8)R^(d8), C(O)OR^(a8), OC(O)R^(b8), OC(O)NR^(c8)R^(d8),NR^(c8)R^(d8), NR^(c8)C(O)R^(b8), NR^(c8)C(O)NR^(c8)R^(d8),NR^(c8)C(O)OR^(a8), C(═NR^(e8))NR^(c8)R^(d8),NR^(c8)C(═NR^(e8))NR^(c8)R^(d8), S(O)R^(b8), S(O)NR^(c8)R^(d8),S(O)₂R^(b8), NR^(c8)S(O)₂R^(b8), NR^(c8)S(O)₂NR^(c8)R^(d8), andS(O)₂NR^(c8)R^(d8); or any R^(c1) and R^(d1) together with the N atom towhich they are attached form a 4-, 5-, 6-, or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3substituents independently selected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl,4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₁₋₆haloalkyl, halo, CN, OR^(a8), SR^(a8), C(O)R^(b8), C(O)NR^(c8)R^(d8),C(O)OR^(a8), OC(O)R^(b8), OC(O)NR^(c8)R^(d8), NR^(c8)R^(d8),NR^(c8)C(O)R^(b8), NR^(c8)C(O)NR^(c8)R^(d8), NR^(c8)C(O)OR^(a8),C(═NR^(e8))NR^(c8)R^(d8), NR^(c8)C(═NR^(e8))NR^(c8)R^(d8), S(O)R^(b8),S(O)NR^(c8)R^(d8), S(O)₂R^(b8), NR^(c8)S(O)₂R^(b8),NR^(c8)S(O)₂NR^(c8)R^(d8), and S(O)₂NR^(c8)R^(d8), wherein said C₁₋₆alkyl, C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, and5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3substituents independently selected from halo, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄ cyanoalkyl, CN, OR^(a8), SR^(a8), C(O)R^(b8),C(O)NR^(c8)R^(d8), C(O)OR^(a8), OC(O)R^(b8), OC(O)NR^(c8)R^(d8),NR^(c8)R^(d8), NR^(c8)C(O)R^(b8), NR^(c8)C(O)NR^(c8)R^(d8),NR^(c8)C(O)OR^(a8), C(═NR^(e8))NR^(c8)R^(d8),NR^(c8)C(═NR^(e8))NR^(c8)R^(d8), S(O)R^(b8), S(O)NR^(c8)R^(d8),S(O)₂R^(b8), NR^(c8)S(O)₂R^(b8), NR^(c8)S(O)₂NR^(c8)R^(d8), andS(O)₂NR^(c8)R^(d8); each R^(a2), R^(b2), R^(c2), and R^(d2) isindependently selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein said C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are each optionallysubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, halo, CN, OR^(a8),SR^(a8), C(O)R^(b8), C(O)NR^(c8)R^(d8), C(O)OR^(a8), OC(O)R^(b8),OC(O)NR^(c8)R^(d8), NR^(c8)R^(d8), NR^(c8)C(O)R^(b8),NR^(c8)C(O)NR^(c8)R^(d8), NR^(c8)C(O)OR^(a8), C(═NR^(e8))NR^(c8)R^(d8),NR^(c8)C(═NR^(e8))NR^(c8)R^(d8), S(O)R^(b8), S(O)NR^(c8)R^(d8),S(O)₂R^(b8), NR^(c8)S(O)₂R^(b8), NR^(c8)S(O)₂NR^(c8)R^(d8), andS(O)₂NR^(c8)R^(d8); or any R^(c2) and R^(d2) together with the N atom towhich they are attached form a 4-, 5-, 6-, or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3substituents independently selected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl,4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₁₋₆haloalkyl, halo, CN, OR^(a8), SR^(a8), C(O)R^(b8), C(O)NR^(c8)R^(d8),C(O)OR^(a8), OC(O)R^(b8), OC(O)NR^(c8)R^(d8), NR^(c8)R^(d8),NR^(c8)C(O)R^(b8), NR^(c8)C(O)NR^(c8)R^(d8), NR^(c8)C(O)OR^(a8),C(═NR^(e8))NR^(c8)R^(d8), NR^(c8)C(═NR^(e8))NR^(c8)R^(d8), S(O)R^(b8),S(O)NR^(c8)R^(d8), S(O)₂R^(b8), NR^(c8)S(O)₂R^(b8),NR^(c8)S(O)₂NR^(c8)R^(d8), and S(O)₂NR^(c8)R^(d8), wherein said C₁₋₆alkyl, C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, and5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3substituents independently selected from halo, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄ cyanoalkyl, CN, OR^(a8), SR^(a8), C(O)R^(b8),C(O)NR^(c8)R^(d8), C(O)OR^(a8), OC(O)R^(b8), OC(O)NR^(c8)R^(d8),NR^(c8)R^(d8), NR^(c8)C(O)R^(b8), NR^(c8)C(O)NR^(c8)R^(d8),NR^(c8)C(O)OR^(a8), C(═NR^(e8))NR^(c8)R^(d8),NR^(c8)C(═NR^(e8))NR^(c8)R^(d8), S(O)R^(b8), S(O)NR^(c8)R^(d8),S(O)₂R^(b8), NR^(c8)S(O)₂R^(b8), NR^(c8)S(O)₂NR^(c8)R^(d8), andS(O)₂NR^(c8)R^(d8); each R^(a3), R^(b3), R^(c3), and R^(d3), isindependently selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein said C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are each optionallysubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, halo, CN, OR^(a8),SR^(a8), C(O)R^(b8), C(O)NR^(c8)R^(d8), C(O)OR^(a8), OC(O)R^(b8),OC(O)NR^(c8)R^(d8), NR^(c8)R^(d8), NR^(c8)C(O)R^(b8),NR^(c8)C(O)NR^(c8)R^(d8), NR^(c8)C(O)OR^(a8), C(═NR^(e8))NR^(c8)R^(d8),NR^(c8)C(═NR^(e8))NR^(c8)R^(d8), S(O)R^(b8), S(O)NR^(c8)R^(d8),S(O)₂R^(b8), NR^(c8)S(O)₂R^(b8), NR^(c8)S(O)₂NR^(c8)R^(d8), andS(O)₂NR^(c8)R^(d8); or any R^(c3) and R^(d3), together with the N atomto which they are attached form a 4-, 5-, 6-, or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3substituents independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,halo, CN, OR^(a8), SR^(a8), C(O)R^(b8), C(O)NR^(c8)R^(d8), C(O)OR^(a8),OC(O)R^(b8), OC(O)NR^(c8)R^(d8), NR^(c8)R^(d8), NR^(c8)C(O)R^(b8),NR^(c8)C(O)NR^(c8)R^(d8), NR^(c8)C(O)OR^(a8), C(═NR^(e8))NR^(c8)R^(d8),NR^(c8)C(═NR^(e8))NR^(c8)R^(d8), S(O)R^(b8), S(O)NR^(c8)R^(d8),S(O)₂R^(b8), NR^(c8)S(O)₂R^(b8), NR^(c8)S(O)₂NR^(c8)R^(d8), andS(O)₂NR^(c8)R^(d8); each R^(a4), R^(b4), R^(c4), and R^(d4) isindependently selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl,and C₂₋₆ alkynyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl are each optionally substituted with 1, 2, 3, 4, or 5substituents independently selected from C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄cyanoalkyl, halo, CN, OR^(a8), SR^(a8), C(O)R^(b8), C(O)NR^(c8)R^(d8),C(O)OR^(a8), OC(O)R^(b8), OC(O)NR^(c8)R^(d8), NR^(c8)R^(d8),NR^(c8)C(O)R^(b8), NR^(c8)C(O)NR^(c8)R^(d8), NR^(c8)C(O)OR^(a8),C(═NR^(e8))NR^(c8)R^(d8), NR^(c8)C(═NR^(e8))NR^(c8)R^(d8), S(O)R^(b8),S(O)NR^(c8)R^(d8), S(O)₂R^(b8), NR^(c8)S(O)₂R^(b8),NR^(c8)S(O)₂NR^(c8)R^(d8), and S(O)₂NR^(c8)R^(d8); or any R^(c4) andR^(d4) together with the N atom to which they are attached form a 4-,5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with1, 2, or 3 substituents independently selected from C₁₋₆ alkyl, C₁₋₆haloalkyl, halo, CN, OR^(a8), SR^(a8), C(O)R^(b8), C(O)NR^(c8)R^(d8),C(O)OR^(a8), OC(O)R^(b8), OC(O)NR^(c8)R^(d8), NR^(c8)R^(d8),NR^(c8)C(O)R^(b8), NR^(c8)C(O)NR^(c8)R^(d8), NR^(c8)C(O)OR^(a8),C(═NR^(e8))NR^(c8)R^(d8), NR^(c8)C(═NR^(e8))NR^(c8)R^(d8), S(O)R^(b8),S(O)NR^(c8)R^(d8), S(O)₂R^(b8), NR^(c8)S(O)₂R^(b8),NR^(c8)S(O)₂NR^(c8)R^(d8), and S(O)₂NR^(c8)R^(d8); each R^(a5), R^(b5),R^(c5), and R^(d5) is independently selected from H, C₁₋₆ alkyl, C₁₋₄haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄alkyl-, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- are each optionally substituted with 1, 2,3, 4, or 5 substituents independently selected from C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄ cyanoalkyl, halo, CN, OR^(a8), SR^(a8), C(O)R^(b8),C(O)NR^(c8)R^(d8), C(O)OR^(a8), OC(O)R^(b8), OC(O)NR^(c8)R^(d8),NR^(c8)R^(d8), NR^(c8)C(O)R^(b8), NR^(c8)C(O)NR^(c8)R^(d8),NR^(c8)C(O)OR^(a8), C(═NR^(e8))NR^(c8)R^(d8),NR^(c8)C(═NR^(e8))N^(c8)R^(d8), S(O)R^(b8), S(O)NR^(c8)R^(d8),S(O)₂R^(b8), NR^(c8)S(O)₂R^(b8), NR^(c8)S(O)₂NR^(c8)R^(d8), andS(O)₂NR^(c8)R^(d8); or any R^(c5) and R^(d5) together with the N atom towhich they are attached form a 4-, 5-, 6-, or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3substituents independently selected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl,4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₁₋₆haloalkyl, halo, CN, OR^(a8), SR^(a8), C(O)R^(b8), C(O)NR^(c8)R^(d8),C(O)OR^(a8), OC(O)R^(b8), OC(O)NR^(c8)R^(d8), NR^(c8)R^(d8),NR^(c8)C(O)R^(b8), NR^(c8)C(O)NR^(c8)R^(d8), NR^(c8)C(O)OR^(a8),C(═NR^(e8))NR^(c8)R^(d8), NR^(c8)C(═NR^(e8))NR^(c8)R^(d8), S(O)R^(b8),S(O)NR^(c8)R^(d8), S(O)₂R^(b8), NR^(c8)S(O)₂R^(b8),NR^(c8)S(O)₂NR^(c8)R^(d8), and S(O)₂NR^(c8)R^(d8), wherein said C₁₋₆alkyl, C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, and5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3substituents independently selected from halo, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄ cyanoalkyl, CN, OR^(a8), SR^(a8), C(O)R^(b8),C(O)NR^(c8)R^(d8), C(O)OR^(a8), OC(O)R^(b8), OC(O)NR^(c8)R^(d8),NR^(c8)R^(d8), NR^(c8)C(O)R^(b8), NR^(c8)C(O)NR^(c8)R^(d8),NR^(c8)C(O)OR^(a8), C(═NR^(e8))NR^(c8)R^(d8),NR^(c8)C(═NR^(e8))NR^(c8)R^(d8), S(O)R^(b8), S(O)NR^(c8)R^(d8),S(O)₂R^(b8), NR^(c8)S(O)₂R^(b8), NR^(c8)S(O)₂NR^(c8)R^(d8), andS(O)₂NR^(c8)R^(d8); each R^(a6), R^(b6), R^(c6), and R^(d6) isindependently selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl,and C₂₋₆ alkynyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl are each optionally substituted with 1, 2, 3, 4, or 5substituents independently selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl,C₁₋₄ cyanoalkyl, halo, CN, OR^(a8), SR^(a8), C(O)R^(b8),C(O)NR^(c8)R^(d8), C(O)OR^(a8), OC(O)R^(b8), OC(O)NR^(c8)R^(d8),NR^(c8)R^(d8), NR^(c8)C(O)R^(b8), NR^(c8)C(O)NR^(c8)R^(d8),NR^(c8)C(O)OR^(a8), C(═NR^(e8))NR^(c8)R^(d8),NR^(c8)C(═NR^(e8))NR^(c8)R^(d8), S(O)R^(b8), S(O)NR^(c8)R^(d8),S(O)₂R^(b8), NR^(c8)S(O)₂R^(b8), NR^(c8)S(O)₂NR^(c8)R^(d8), andS(O)₂NR^(c8)R^(d8); or any R^(c6) and R^(d6) together with the N atom towhich they are attached form a 4-, 5-, 6-, or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3substituents independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,halo, CN, OR^(a8), SR^(a8), C(O)R^(b8), C(O)NR^(c8)R^(d8), C(O)OR^(a8),OC(O)R^(b8), OC(O)NR^(c8)R^(d8), NR^(c8)R^(d8), NR^(c8)C(O)R^(b8),NR^(c8)C(O)NR^(c8)R^(d8), NR^(c8)C(O)OR^(a8), C(═NR^(e8))NR^(c8)R^(d8),NR^(c8)C(═NR^(e8))NR^(c8)R^(d8), S(O)R^(b8), S(O)NR^(c8)R^(d8),S(O)₂R^(b8), NR^(c8)S(O)₂R^(b8), NR^(c8)S(O)₂NR^(c8)R^(d8), andS(O)₂NR^(c8)R^(d8); each R^(a7), R^(b7), R^(c7), and R^(d7) isindependently selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein said C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are each optionallysubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, halo, CN, OR^(a8),SR^(a8), C(O)R^(b8), C(O)NR^(c8)R^(d8), C(O)OR^(a8), OC(O)R^(b8),OC(O)NR^(c8)R^(d8), NR^(c8)R^(d8), NR^(c8)C(O)R^(b8),NR^(c8)C(O)NR^(c8)R^(d8), NR^(c8)C(O)OR^(a8), C(═NR^(e8))NR^(c8)R^(d8),NR^(c8)C(═NR^(e8))NR^(c8)R^(d8), S(O)R^(b8), S(O)NR^(c8)R^(d8),S(O)₂R^(b8), NR^(c8)S(O)₂R^(b8), NR^(c8)S(O)₂NR^(c8)R^(d8), andS(O)₂NR^(c8)R^(d8); or any R^(c7) and R^(d7) together with the N atom towhich they are attached form a 4-, 5-, 6-, or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3substituents independently selected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl,4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₁₋₆haloalkyl, halo, CN, OR^(a8), SR^(a8), C(O)R^(b8), C(O)NR^(c8)R^(d8),C(O)OR^(a8), OC(O)R^(b8), OC(O)NR^(c8)R^(d8), NR^(c8)R^(d8),NR^(c8)C(O)R^(b8), NR^(c8)C(O)NR^(c8)R^(d8), NR^(c8)C(O)OR^(a8),C(═NR^(e8))NR^(c8)R^(d8), NR^(c8)C(═NR^(e8))NR^(c8)R^(d8), S(O)R^(b8),S(O)NR^(c8)R^(d8), S(O)₂R^(b8), NR^(c8)S(O)₂R^(b8),NR^(c8)S(O)₂NR^(c8)R^(d8), and S(O)₂NR^(c8)R^(d8), wherein said C₁₋₆alkyl, C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, and5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3substituents independently selected from halo, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄ cyanoalkyl, CN, OR^(a8), SR^(a8), C(O)R^(b8),C(O)NR^(c8)R^(d8), C(O)OR^(a8), OC(O)R^(b8), OC(O)NR^(c8)R^(d8),NR^(c8)R^(d8), NR^(c8)C(O)R^(b8), NR^(c8)C(O)NR^(c8)R^(d8),NR^(c8)C(O)OR^(a8), C(═NR^(e8))NR^(c8)R^(d8),NR^(c8)C(═NR^(e8))NR^(c8)R^(d8), S(O)R^(b8), S(O)NR^(c8)R^(d8),S(O)₂R^(b8), NR^(c8)S(O)₂R^(b8), NR^(c8)S(O)₂NR^(c8)R^(d8), andS(O)₂NR^(c8)R^(d8); each R^(a8), R^(b8), R^(e8), and R^(d8) isindependently selected from H, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₄ alkenyl,and C₂₋₄ alkynyl, wherein said C₁₋₄ alkyl, C₂₋₄ alkenyl, and C₂₋₄alkynyl are each optionally substituted with 1, 2, or 3 substituentsindependently selected from OH, CN, amino, halo, C₁₋₄ alkyl, C₁₋₄alkoxy, C₁₋₄ alkylthio, C₁₋₄ alkylamino, di(C₁₋₄ alkyl)amino, C₁₋₄haloalkyl, and C₁₋₄ haloalkoxy; and each R^(e1), R^(e2), R^(e3), R^(e4),R^(e5), R^(e6), R^(e7), and R^(e8) is independently selected from H,C₁₋₄ alkyl, and CN; wherein when X is N; then Ring A is substituted byat least one R^(A) or Ring B is substituted by at least one R^(B). 42.The method of claim 41 wherein said cancer is a hematological cancer.43. The method of claim 42 wherein said hematological cancer is selectedfrom acute lymphoblastic leukemia (ALL), acute myelogenous leukemia(AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia(CLL), chronic myelogenous leukemia (CML), diffuse large B-cell lymphoma(DLBCL), mantle cell lymphoma, Non-Hodgkin lymphoma (including relapsedor refractory NHL and recurrent follicular), Hodgkin lymphoma, primarymyelofibrosis (PMF), polycythemia vera (PV), essential thrombocytosis(ET)), myelodysplasia syndrome (MDS), or multiple myeloma.
 44. Themethod of claim 41 wherein said cancer is a sarcoma, lung cancer,gastrointestinal cancer, genitourinary tract cancer, liver cancer, bonecancer, nervous system cancer, gynecological cancer, or skin cancer. 45.(canceled)
 46. The method of claim 1, wherein: X is N or CR^(X); Y is(a) C═O and Z is NR^(Z) or (b) Y is CR³ and Z is N; wherein the bondbetween Y and Z represented by

is a single bond in the case of (a) and a double bond in the case of(b); Ring A is phenyl optionally substituted by 1 or 2 substituentsindependently selected from R^(A); Ring B is phenyl optionallysubstituted by 1 or 2 substituents independently selected from R^(B); R¹is OR^(a1); R³ is H; each R^(A) is independently selected from halo,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, CN, NO₂,OR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4), NR^(c4)R^(d4),NR^(c4)C(O)R^(b4), S(O)₂R^(b4), and S(O)₂NR^(c4)R^(d4), wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are each optionallysubstituted by 1, 2, or 3, substituents independently selected fromhalo, C₁₋₆ haloalkyl, CN, NO₂, OR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4),C(O)OR^(a4), NR^(c4)R^(d4) NR^(c4)C(O)R^(b4), S(O)₂R^(b4), andS(O)₂NR^(c4)R^(d4); each R^(B) is independently selected from halo, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, CN, NO₂, OR^(a5),C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5), NR^(c5)R^(d5),NR^(c5)C(O)R^(b5), S(O)₂R^(b5), and S(O)₂NR^(c5)R^(d5), wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are each optionallysubstituted by 1, 2, or 3 substituents independently selected from halo,C₁₋₆ haloalkyl, CN, NO₂, OR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5),C(O)OR^(a5), NR^(c5)R^(d5), NR^(c5)C(O)R^(b5), S(O)₂R^(b5), andS(O)₂NR^(c5)R^(d5); R^(X) is H; R^(Z) is H, C₁₋₆ alkyl, or C₁₋₆haloalkyl, wherein said C₁₋₆ alkyl is optionally substituted with 1, 2,3, 4, or 5 substituents independently selected from Cy⁴, halo, CN,OR^(a3), C(O)NR^(c3)R^(d3), and NR^(c3)R^(d3); each Cy⁴ is independentlyselected from phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, and 4-7membered heterocycloalkyl, each of which is optionally substituted with1 or 2 substituents independently selected from R^(Cy); each Cy⁵ isindependently selected from 4-7 membered heterocycloalkyl, each of whichis optionally substituted with 1 or 2 substituents independentlyselected from R^(Cy); each R^(Cy) is selected from halo, C₁₋₄ alkyl,C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, CN, NO₂, OR^(a6), C(O)R^(b6),C(O)NR^(c6)R^(d6), C(O)OR^(a6), NR^(c6)R^(d6), NR^(c6)C(O)R^(b6),S(O)₂R^(b6), and S(O)₂NR^(c6)R^(d6); each R^(a1) is C₁₋₆ alkyloptionally substituted with Cy⁵; each R^(a3), R³, and R^(d3), isindependently selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein said C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are each optionallysubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, halo, CN, OR^(a8),SR^(a8), C(O)R^(b8), C(O)NR^(c8)R^(d8), C(O)OR^(a8), OC(O)R^(b8),OC(O)NR^(c8)R^(d8), NR^(c8)R^(d8), NR^(c8)C(O)R^(b8),NR^(c8)C(O)NR^(c8)R^(d8), NR^(c8)C(O)OR^(a8), C(═NR^(e8))NR^(c8)R^(d8),NR^(c8)C(═NR^(e8))NR^(c8)R^(d8), S(O)R^(b8), S(O)NR^(c8)R^(d8),S(O)₂R^(b8), NR^(c8)S(O)₂R^(b8), NR^(c8)S(O)₂NR^(c8)R^(d8), andS(O)₂NR^(c8)R^(d8); or any R^(c3) and R^(d3), together with the N atomto which they are attached form a 4-, 5-, 6-, or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3substituents independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,halo, CN, OR^(a8), SR^(a8), C(O)R^(b8), C(O)NR^(c8)R^(d8), C(O)OR^(a8),OC(O)R^(b8), OC(O)NR^(c8)R^(d8), NR^(c8)R^(d8), NR^(c8)C(O)R^(b8),NR^(c8)C(O)NR^(c8)R^(d8), NR^(c8)C(O)OR^(a8), C(═NR^(e8))NR^(c8)R^(d8),NR^(c8)C(═NR^(e8))NR^(c8)R^(d8), S(O)R^(b8), S(O)NR^(c8)R^(d8),S(O)₂R^(b8), NR^(c8)S(O)₂R^(b8), NR^(c8)S(O)₂NR^(c8)R^(d8), andS(O)₂NR^(c8)R^(d8); each R^(a4), R^(b4), R^(c4), and R^(d4) isindependently selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl,and C₂₋₆ alkynyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl are each optionally substituted with 1, 2, 3, 4, or 5substituents independently selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl,C₁₋₄ cyanoalkyl, halo, CN, OR^(a8), SR^(a8), C(O)R^(b8),C(O)NR^(c8)R^(d8), C(O)OR^(a8), OC(O)R^(b8), OC(O)NR^(c8)R^(d8),NR^(c8)R^(d8), NR^(c8)C(O)R^(b8), NR^(c8)C(O)NR^(c8)R^(d8),NR^(c8)C(O)OR^(a8), C(═NR^(e8))NR^(c8)R^(d8),NR^(c8)C(═NR^(e8))NR^(c8)R^(d8), S(O)R^(b8), S(O)NR^(c8)R^(d8),S(O)₂R^(b8), NR^(c8)S(O)₂R^(b8), NR^(c8)S(O)₂NR^(c8)R^(d8), andS(O)₂NR^(c8)R^(d8); or any R^(c4) and R^(d4) together with the N atom towhich they are attached form a 4-, 5-, 6-, or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3substituents independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,halo, CN, OR^(a8), SR^(a8), C(O)R^(b8), C(O)NR^(c8)R^(d8), C(O)OR^(a8),OC(O)R^(b8), OC(O)NR^(c8)R^(d8), NR^(c8)R^(d8), NR^(c8)C(O)R^(b8),NR^(c8)C(O)NR^(c8)R^(d8), NR^(c8)C(O)OR^(a8), C(═NR^(e8))NR^(c8)R^(d8),NR^(c8)C(═NR^(e5))N^(c8)R^(d8), S(O)R^(b8), S(O)NR^(c8)R^(d8),S(O)₂R^(b8), NR^(c8)S(O)₂R^(b8), NR^(c8)S(O)₂NR^(c8)R^(d8), andS(O)₂NR^(c8)R^(d8); each R^(a5), R^(b5), R^(c5), and R^(d5) isindependently selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein said C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are each optionallysubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, halo, CN, OR^(a8),SR^(a8), C(O)R^(b8), C(O)NR^(c8)R^(d8), C(O)OR^(a8), OC(O)R^(b8),OC(O)NR^(c8)R^(d8), NR^(c8)R^(d8), NR^(c8)C(O)R^(b8),NR^(c8)C(O)NR^(c8)R^(d8), NR^(c8)C(O)OR^(a8), C(═NR^(e8))NR^(c8)R^(d8),NR^(c8)C(═NR^(e8))NR^(c8)R^(d8), S(O)R^(b8), S(O)NR^(c8)R^(d8),S(O)₂R^(b8), NR^(c8)S(O)₂R^(b8), NR^(c8)S(O)₂NR^(c8)R^(d8), andS(O)₂NR^(c8)R^(d8); or any R^(c5) and R^(d5) together with the N atom towhich they are attached form a 4-, 5-, 6-, or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3substituents independently selected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl,4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₁₋₆haloalkyl, halo, CN, OR^(a8), SR^(a8), C(O)R^(b8), C(O)NR^(c8)R^(d8),C(O)OR^(a8), OC(O)R^(b8), OC(O)NR^(c8)R^(d8), NR^(c8)R^(d8),NR^(c8)C(O)R^(b8), NR^(c8)C(O)NR^(c8)R^(d8), NR^(c8)C(O)OR^(a8),C(═NR^(e8))NR^(c8)R^(d8), NR^(c8)C(═NR^(e8))NR^(c8)R^(d8), S(O)R^(b8),S(O)NR^(c8)R^(d8), S(O)₂R^(b8), NR^(c8)S(O)₂R^(b8),NR^(c8)S(O)₂NR^(c8)R^(d8), and S(O)₂NR^(c8)R^(d8), wherein said C₁₋₆alkyl, C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, and5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3substituents independently selected from halo, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄ cyanoalkyl, CN, OR^(a8), SR^(a8), C(O)R^(b8),C(O)NR^(c8)R^(d8), C(O)OR^(a8), OC(O)R^(b8), OC(O)NR^(c8)R^(d8),NR^(c8)R^(d8), NR^(c8)C(O)R^(b8), NR^(c8)C(O)NR^(c8)R^(d8),NR^(c8)C(O)OR^(a8), C(═NR^(e8))NR^(c8)R^(d8),NR^(c5)C(═NR^(e8))NR^(c8)R^(d8), S(O)R^(b8), S(O)NR^(c8)R^(d8),S(O)₂R^(b8), NR^(c8)S(O)₂R^(b8), NR^(c8)S(O)₂NR^(c8)R^(d8), andS(O)₂NR^(c8)R^(d8); each R^(a6), R^(b6), R^(c6), and R^(d6) isindependently selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl,and C₂₋₆ alkynyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl are each optionally substituted with 1, 2, 3, 4, or 5substituents independently selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl,C₁₋₄ cyanoalkyl, halo, CN, OR^(a8), SR^(a8), C(O)R^(b8),C(O)NR^(c8)R^(d8), C(O)OR^(a8), OC(O)R^(b8), OC(O)NR^(c8)R^(d8),NR^(c8)R^(d8), NR^(c8)C(O)R^(b8), NR^(c8)C(O)NR^(c8)R^(d8),NR^(c8)C(O)OR^(a8), C(═NR^(e8))NR^(c8)R^(d8),NR^(c8)C(═NR^(e8))NR^(c8)R^(d8), S(O)R^(b8), S(O)NR^(c8)R^(d8),S(O)₂R^(b8), NR^(c8)S(O)₂R^(b8), NR^(c8)S(O)₂NR^(c8)R^(d8), andS(O)₂NR^(c8)R^(d8); or any R^(c6) and R^(d6) together with the N atom towhich they are attached form a 4-, 5-, 6-, or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3substituents independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,halo, CN, OR^(a8), SR^(a8), C(O)R^(b8), C(O)NR^(c8)R^(d8), C(O)OR^(a8),OC(O)R^(b8), OC(O)NR^(c8)R^(d8), NR^(c8)R^(d8), NR^(c8)C(O)R^(b8),NR^(c8)C(O)NR^(c8)R^(d8), NR^(c8)C(O)OR^(a8), C(═NR^(e8))NR^(c8)R^(d8),NR^(c8)C(═NR^(e8))NR^(c8)R^(d8), S(O)R^(b8), S(O)NR^(c8)R^(d8),S(O)₂R^(b8), NR^(c8)S(O)₂R^(b8), NR^(c8)S(O)₂NR^(c8)R^(d8), andS(O)₂NR^(c8)R^(d8); each R^(a8), R^(b8), R^(c8), and R^(d8) isindependently selected from H, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₄ alkenyl,and C₂₋₄ alkynyl, wherein said C₁₋₄ alkyl, C₂₋₄ alkenyl, and C₂₋₄alkynyl are each optionally substituted with 1, 2, or 3 substituentsindependently selected from OH, CN, amino, halo, C₁₋₄ alkyl, C₁₋₄alkoxy, C₁₋₄ alkylthio, C₁₋₄ alkylamino, di(C₁₋₄ alkyl)amino, C₁₋₄haloalkyl, and C₁₋₄ haloalkoxy; and each R^(e8) is independentlyselected from H, C₁₋₄ alkyl, and CN; wherein when X is N; then Ring A issubstituted by at least one R^(A) or Ring B is substituted by at leastone R^(B).
 47. The method of claim 1, wherein Ring A is phenyloptionally substituted by 1 or 2 substituents independently selectedfrom R^(A).
 48. The method of claim 1, wherein Ring B is C₆₋₁₀ aryloptionally substituted by 1, 2, 3, or 4 substituents independentlyselected from R^(B).
 49. The method of claim 1, wherein Ring B is phenyloptionally substituted by 1 or 2 substituents independently selectedfrom R^(B).
 50. The method of claim 1, wherein R^(Z) is H, C₁₋₄ alkyl,or C₁₋₆ haloalkyl, wherein said C₁₋₄ alkyl is optionally substitutedwith 1, 2, 3, 4, or 5 substituents independently selected from OH, CN,F, phenyl, C₃₋₇ cyclalkyl, 5-6 membered heterocycloalkyl, 5-6 memberedheteroaryl, C(O)NH₂, phenoxy, and dimethylamino, wherein said phenyl isoptionally substituted by CN and said pyrazolyl is optionallysubstituted by methyl.
 51. The method of claim 1, wherein R^(Z) is H,methyl, cyanomethyl, cyanoethyl, cyclopentylmethyl,tetrahydrofuranylmethyl, (1-methyl-1H-pyrazol-3-yl)methyl,morpholinylethyl, aminocarbonylmethyl, 3,3,3-trifluoro-2-hydroxypropyl,piperidinylmethyl, phenoxyethyl, dimethylaminoethyl, benzyl,cyanophenyl, or hydroxyethyl.
 52. The method of claim 1, wherein R^(A)is CN.
 53. The method of claim 1, wherein R^(B) is C₁₋₆ alkyl.
 54. Themethod of claim 1, wherein R^(B) is methyl.
 55. The method of claim 1,wherein each R^(a1) is pyrrolidinylmethyl.
 56. The method of claim 1,wherein Cy⁴ is phenyl, cyclopentyl, tetrahydrofuranyl, pyrazolyl,morpholinyl, or piperidinyl, each optionally substituted by onesubstituent independently selected from methyl and CN.
 57. The method ofclaim 1, wherein Cy⁵ is pyrrolidinyl.
 58. The method of claim 1, whereinthe compound is a compound of Formula IVa:

or a pharmaceutically acceptable salt thereof, wherein: n is 0, 1, 2, 3,or 4; and m is 0, 1, 2, 3, or
 4. 59. The method of claim 1, wherein thecompound is a compound of Formula IVb:

or a pharmaceutically acceptable salt thereof, wherein: n is 0, 1, 2, 3,or 4; and m is 0, 1, 2, 3, or
 4. 60. The method of claim 1, wherein thecompound is selected from:4-{5-(4-methylphenyl)-8-[(3R)-pyrrolidin-3-ylmethoxy][1,2,4]triazolo[4,3-a]pyridin-6-yl}benzonitrile;2-fluoro-4-{5-(4-methylphenyl)-8-[(3R)-pyrrolidin-3-ylmethoxy][1,2,4]triazolo[4,3-a]pyridin-6-yl}benzonitrile;4-{5-(4-methylphenyl)-3-oxo-8-[(3R)-pyrrolidin-3-ylmethoxy]-2,3-dihydro[1,2,4]triazolo[4,3-a]pyridin-6-yl}benzonitrile;4-{2-methyl-5-(4-methylphenyl)-3-oxo-8-[(3R)-pyrrolidin-3-ylmethoxy]-2,3-dihydro[1,2,4]triazolo[4,3-a]pyridin-6-yl}benzonitrile;(R)-4-(2-(cyanomethyl)-3-oxo-8-(pyrrolidin-3-ylmethoxy)-5-p-tolyl-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-6-yl)benzonitrile;4-{2-(2-cyanoethyl)-5-(4-methylphenyl)-3-oxo-8-[(3R)-pyrrolidin-3-ylmethoxy]-2,3-dihydro[1,2,4]triazolo[4,3-a]pyridin-6-yl}benzonitrile;4-{2-(cyclopentylmethyl)-5-(4-methylphenyl)-3-oxo-8-[(3R)-pyrrolidin-3-ylmethoxy]-2,3-dihydro[1,2,4]triazolo[4,3-a]pyridin-6-yl}benzonitrile;4-[5-(4-methylphenyl)-3-oxo-8-[(3R)-pyrrolidin-3-ylmethoxy]-2-(tetrahydrofuran-2-ylmethyl)-2,3-dihydro[1,2,4]triazolo[4,3-a]pyridin-6-yl]benzonitrile;4-{5-(4-methylphenyl)-2-[(1-methyl-1H-pyrazol-3-yl)methyl]-3-oxo-8-[(3R)-pyrrolidin-3-ylmethoxy]-2,3-dihydro[1,2,4]triazolo[4,3-a]pyridin-6-yl}benzonitrile;4-{5-(4-methylphenyl)-2-(2-morpholin-4-ylethyl)-3-oxo-8-[(3R)-pyrrolidin-3-ylmethoxy]-2,3-dihydro[1,2,4]triazolo[4,3-a]pyridin-6-yl}benzonitrile;2-[6-(4-cyanophenyl)-5-(4-methylphenyl)-3-oxo-8-[(3R)-pyrrolidin-3-ylmethoxy][1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl]acetamide;4-[5-(4-methylphenyl)-3-oxo-8-[(3R)-pyrrolidin-3-ylmethoxy]-2-(3,3,3-trifluoro-2-hydroxypropyl)-2,3-dihydro[1,2,4]triazolo[4,3-a]pyridin-6-yl]benzonitrile;4-{5-(4-methylphenyl)-3-oxo-2-(piperidin-4-ylmethyl)-8-[(3R)-pyrrolidin-3-ylmethoxy]-2,3-dihydro[1,2,4]triazolo[4,3-a]pyridin-6-yl}benzonitrile;4-{5-(4-methylphenyl)-3-oxo-2-(2-phenoxyethyl)-8-[(3R)-pyrrolidin-3-ylmethoxy]-2,3-dihydro[1,2,4]triazolo[4,3-a]pyridin-6-yl}benzonitrile;4-{2-[2-(dimethylamino)ethyl]-5-(4-methylphenyl)-3-oxo-8-[(3R)-pyrrolidin-3-ylmethoxy]-2,3-dihydro[1,2,4]triazolo[4,3-a]pyridin-6-yl}benzonitrile;4-{2-benzyl-5-(4-methylphenyl)-3-oxo-8-[(3R)-pyrrolidin-3-ylmethoxy]-2,3-dihydro[1,2,4]triazolo[4,3-a]pyridin-6-yl}benzonitrile;4-{2-(4-cyanobenzyl)-5-(4-methylphenyl)-3-oxo-8-[(3R)-pyrrolidin-3-ylmethoxy]-2,3-dihydro[1,2,4]triazolo[4,3-a]pyridin-6-yl}benzonitrile;4-{2-(2-hydroxyethyl)-5-(4-methylphenyl)-3-oxo-8-[(3R)-pyrrolidin-3-ylmethoxy]-2,3-dihydro[1,2,4]triazolo[4,3-a]pyridin-6-yl}benzonitrile;4-{5-(4-methylphenyl)-8-[(3R)-pyrrolidin-3-ylmethoxy][1,2,4]triazolo[4,3-a]pyrazin-6-yl}benzonitrile;and4-{5-(4-methylphenyl)-3-oxo-8-[(3R)-pyrrolidin-3-ylmethoxy]-2,3-dihydro[1,2,4]triazolo[4,3-a]pyrazin-6-yl}benzonitrile;or a pharmaceutically acceptable salt of any of the aforementioned.